Compositions and methods for modulating short-chain dehydrogenase activity

文档序号：1712627 发布日期：2019-12-13 浏览：22次中文

阅读说明：本技术 调节短链脱氢酶活性的组合物和方法 (Compositions and methods for modulating short-chain dehydrogenase activity ) 是由 S·D·马科维茨原一源张咏佑 J·雷迪胡斌于 2018-02-06 设计创作，主要内容包括：本发明提供了调节15-PGDH活性,调节组织前列腺素水平,治疗需要调节15-PGDH活性和/或前列腺素水平的疾病、疾病紊乱或病症的化合物和方法,包括本文所述的15-PGDH抑制剂。(The present invention provides compounds and methods for modulating 15-PGDH activity, modulating tissue prostaglandin levels, treating diseases, disease disorders, or conditions requiring modulation of 15-PGDH activity and/or prostaglandin levels, comprising a 15-PGDH inhibitor as described herein.)

1. A compound for inhibiting short chain dehydrogenase activity, the compound comprising at least one of formula (I) or (II):

Wherein X¹is N or CR⁴；

X²is S, S ═ O, S (═ O)₂or C ═ O;

X³Is CR⁸Said compound forming a polycyclic heteroaryl group having 10 ring atoms, or X³Absent, the compound forms a polycyclic heteroaryl group having 9 ring atoms;

X⁴Is N, NH or CR⁷；

X⁵Is N, C ═ O or CR¹⁶And if X⁴Is CR⁷Or X³Is absent, X⁵Is N; if X is⁵Is C ═ O, X⁴Is NH; and if X⁴Is N and X³Is CR⁸，X⁵is CR¹⁶；

R¹、R²、R³、R⁴、R⁹、R¹⁰And R¹⁶Are the same or different and are independently selected from the group consisting of hydrogen, oxygen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₀Aryl, heterocycloalkenyl containing 5-7 ring atoms (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of the ring atoms are independently selected from N, NH, N (C)₁-C₃Alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀Aryloxy, acyl (including C)₂-C₂₄alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO)^-) Carbamoyl (- (CO) -NH)₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄Alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀Aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄Alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkyl radicalSulfonyl (-SO)₂Alkyl), C₅-C₂₀Arylsulfonyl (-SO)₂Aryl), sulfonamides (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH)₂)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]Groups comprising amino acids or other moieties predicted to carry a positive or negative charge at physiological pH, and combinations thereof;

R⁷And R⁸Are the same or different and are each independently selected from the group consisting of H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclyl, and R is⁷Or R⁸at least one of which is not H;

And pharmaceutically acceptable salts thereof.

2. The compound of claim 1, comprising at least one of the following formulas:

Wherein X²Is S, S ═ O, S (═ O)₂Or C ═ O;

X⁶Is Cl, Br or F, and y + z ═ 3;

R¹、R²、R³、R⁵、R⁶And R¹⁴Are the same or different and are independently selected from hydrogen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₀Aryl, heterocycloalkenyl containing 5-7 ring atoms (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of the ring atoms are independently selected from N, NH, N (C)₁-C₃Alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀Aryloxy, acyl (including C)₂-C₂₄Alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO)^-) Carbamoyl (- (CO) -NH)₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀Aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, etcAlkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄Alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂Alkyl), C₅-C₂₀Arylsulfonyl (-SO)₂Aryl), sulfonamides (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH)₂)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]Groups comprising amino acids or other moieties predicted to carry a positive or negative charge at physiological pH, and combinations thereof; wherein R is⁵and R⁶May be linked to form a ring or a polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl, n¹Is 0 to 4, and each R¹⁴Are the same or different;

And pharmaceutically acceptable salts thereof.

3. The compound of any one of claims 1 to 2, wherein the compound has a formula selected from the group consisting of:

And pharmaceutically acceptable salts thereof.

4. The compound of claim 1, comprising at least one of the following formulas:

Wherein X⁷Is S, S ═ O, S (═ O)₂or C ═ O;

R⁹、R¹⁰、R¹¹、R¹²、R¹³And R¹⁵are the same or different and are independently selected from the group consisting of hydrogen, oxygen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₀Aryl, heterocycloalkenyl containing 5-7 ring atoms (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of the ring atoms are independently selected from N, NH, N (C)₁-C₃Alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, haloelement, silyl, hydroxy, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀Aryloxy, acyl (including C)₂-C₂₄alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO)^-) Carbamoyl (- (CO) -NH)₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄Alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀Aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄Alkylthio (-S-alkyl; also known as"alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂Alkyl), C₅-C₂₀Arylsulfonyl (-SO)₂Aryl), sulfonamides (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH)₂)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]Groups comprising amino acids or other moieties predicted to carry a positive or negative charge at physiological pH, and combinations thereof; wherein R is¹²And R¹³May be linked to form a ring or a polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl, n²Is 0 to 4, and each R¹⁵Are the same or different;

And pharmaceutically acceptable salts thereof.

5. The compound of claim 1 or 4, having a formula selected from the group consisting of:

And pharmaceutically acceptable salts thereof.

6. a compound according to any one of claims 1 to 5 for use in inhibiting the activity of 15-PGDH enzyme.

7. The compound of any one of claims 1 to 5 with an IC of less than 1 μ M at a recombinant 15-PGDH concentration of about 5nM to about 10nM₅₀Or preferably less than 250nM IC₅₀Or more preferably less than 50nM₅₀Or more preferably less than 10nM IC₅₀Or more preferably less than 5nM IC₅₀Inhibiting the enzymatic activity of recombinant 15-PGDH.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7.

9. The composition of claim 8, administered to a tissue of a subject in an amount effective to increase prostaglandin levels in the tissue.

10. The composition of claim 8, which is a topical composition.

11. The composition of claim 8, which is applied to the skin of a subject, thereby promoting and/or stimulating pigmentation, and/or hair growth, and/or inhibiting hair loss, and/or treating skin damage or inflammation.

12. The composition of claim 8, which is administered to a subject, thereby promoting wound healing, tissue repair and/or tissue regeneration.

13. The composition of claim 8, which is administered to a subject, thereby treating at least one of oral ulcers, gum diseases, colitis, ulcerative colitis, gastroduodenal ulcers, inflammatory bowel disease, vascular insufficiency, raynaud's disease, buerger's disease, diabetic neuropathy, pulmonary hypertension, cardiovascular disease, and renal disease.

14. The composition of claim 8, which is administered to a subject in combination with a prostanoid agonist for the purpose of enhancing the therapeutic effect of the agonist in a prostaglandin responsive condition.

15. The composition of claim 8, which is administered to a tissue of the subject, thereby increasing tissue stem cells.

16. The composition of claim 8, which is administered to a tissue graft donor, a bone marrow graft donor, and/or a hematopoietic stem cell donor, thereby increasing the fitness of the donor tissue graft, the donor bone marrow graft, and/or the donor hematopoietic stem cell graft.

17. The composition of claim 8, which is administered to bone marrow of a subject, thereby increasing stem cells of the subject.

18. The composition of claim 8, which is administered to bone marrow of a subject, thereby increasing the fitness of the bone marrow as a donor graft.

19. The composition of claim 8, which is administered to a preparation of hematopoietic stem cells of a subject, thereby increasing the fitness of the preparation of stem cells as a donor graft.

20. The composition of claim 8, which is administered to a preparation of peripheral blood hematopoietic stem cells of a subject, thereby increasing the suitability of the preparation of stem cells as a donor graft.

21. The composition of claim 8, which is administered to a preparation of cord blood stem cells, thereby increasing the suitability of the preparation of stem cells as a donor graft.

22. The composition of claim 8, which is administered to a preparation of cord blood stem cells, thereby reducing the number of units of cord blood required for transplantation.

23. The composition of claim 8, which is administered to a subject, thereby alleviating rejection of a tissue transplant.

24. The composition of claim 8, which is administered to a subject, thereby increasing implantation of a tissue and/or bone marrow graft.

25. The composition of claim 8, which is administered to a subject, thereby increasing engraftment of a bone marrow transplant following treatment of said subject or bone marrow of said subject with radiation therapy, chemotherapy, or immunosuppressive therapy.

26. The composition of claim 8, which is administered to a subject, thereby increasing engraftment of a progenitor stem cell graft, a hematopoietic stem cell graft, or an umbilical cord stem cell graft.

27. the composition of claim 8, which is administered to a subject, thereby increasing engraftment of a hematopoietic stem cell graft or an umbilical cord blood stem cell graft following treatment of the subject or the subject's bone marrow with radiation therapy, chemotherapy, or immunosuppressive therapy.

28. The composition of claim 8, which is administered to a subject, thereby reducing the number of units of cord blood required for transplantation into the subject.

29. The composition of claim 8, which is administered to a recipient of a tissue transplant, bone marrow transplant and/or hematopoietic stem cell transplant, or a recipient of an umbilical cord blood stem cell transplant, thereby reducing the administration of other therapies or growth factors.

30. The composition of claim 8, which is administered to a subject or a tissue graft of a subject, thereby alleviating graft rejection.

31. The composition of claim 8, which is administered to a subject or a tissue graft of a subject, thereby enhancing implantation of the graft.

32. The composition of claim 8, which is administered to a subject or a tissue graft of a subject, thereby enhancing implantation of the graft after treatment of the subject or bone marrow of the subject with radiation therapy, chemotherapy, or immunosuppressive therapy.

33. The composition of claim 8, which is administered to a subject or bone marrow of a subject, thereby conferring resistance to toxic or lethal effects of exposure to radiation.

34. The composition of claim 8, which is administered to a subject or bone marrow of a subject, thereby conferring resistance to toxic effects of cyclophosphamide, fludarabine, chemotherapy, or immunosuppressive therapy.

35. The composition of claim 8, which is administered to a subject or bone marrow of a subject, thereby reducing infection.

36. The composition of claim 8, which is administered to a subject, thereby increasing neutrophil count following hematopoietic cell transplantation using bone marrow, hematopoietic stem cells or umbilical cord blood.

37. The composition of claim 8, which is administered to a subject, thereby increasing the neutrophil count of a neutropenic subject following chemotherapy administration or radiation therapy.

38. The composition of claim 8, which is administered to a subject suffering from aplastic anemia, myelodysplasia, myelofibrosis, neutropenia due to other bone marrow diseases, drug-induced neutropenia, autoimmune neutropenia, idiopathic neutropenia, or neutropenia post viral infection, thereby increasing the neutrophil count in the subject.

39. The composition of claim 8, which is administered to a subject, thereby increasing neutrophil count in a neutropenic subject.

40. The composition of claim 8, which is administered to a subject, thereby increasing platelet count following hematopoietic cell transplantation using bone marrow, hematopoietic stem cells, or umbilical cord blood.

41. The composition of claim 8, which is administered to a subject, thereby increasing platelet count in a thrombocytopenic subject following chemotherapy administration or radiation therapy.

42. The composition of claim 8, which is administered to a subject suffering from aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia due to other bone marrow diseases, drug-induced thrombocytopenia, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, or thrombocytopenia following viral infection, thereby increasing the platelet count in the subject.

43. the composition of claim 8, which is administered to a subject, thereby increasing the blood cell count of a thrombocytopenic subject.

44. The composition of claim 8, which is administered to a subject, thereby increasing red blood cell count, hematocrit, or hemoglobin level after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells, or umbilical cord blood.

45. The composition of claim 8, which is administered to a subject, thereby increasing red blood cell count, hematocrit, or hemoglobin level of the anemic subject following chemotherapy administration or radiation therapy.

46. The composition of claim 8, which is administered to a subject having aplastic anemia, myelodysplasia, myelofibrosis, anemia due to other disorders of the bone marrow, drug-induced anemia, immune-mediated anemia, anemia of chronic disease, anemia following viral infection, or anemia of unknown origin, thereby increasing the red blood cell count, red blood cell ratio, or hemoglobin level count of the subject.

47. The composition of claim 8, which is administered to a subject, thereby increasing red blood cell count, red blood cell ratio, or hemoglobin level in an anemic subject.

48. The composition of claim 8, which is administered to a subject, thereby increasing bone marrow stem cells after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells or umbilical cord blood.

49. The composition of claim 8, which is administered to a subject, thereby increasing bone marrow stem cells in the subject following chemotherapy administration or radiation therapy.

50. The composition of claim 8, which is administered to a subject suffering from aplastic anemia, myelodysplasia, myelofibrosis, other disorders of the bone marrow, drug-induced cytopenia, immunocytopenia, cytopenia after viral infection, or cytopenia, thereby increasing bone marrow stem cells in a subject.

51. The composition of claim 8, which is administered to a subject, thereby increasing a response to a cytokine in the presence of cytopenia, wherein cytopenia comprises any one of: neutropenia, thrombocytopenia, lymphopenia and anemia; and the cytokine has an increased response potentiated by a 15-PGDH inhibitor, comprising any one of: G-CSF, GM-CSF, EPO, IL-3, IL-6, TPO-RA (thrombopoietin receptor agonist) and SCF.

52. The composition of claim 8, which is administered to a subject or bone marrow of a subject, thereby reducing radiation-induced pulmonary toxicity.

53. The composition of claim 8, which is administered to a subject to increase bone density, treat osteoporosis, promote healing of a bone fracture, or promote healing after bone surgery or joint replacement.

54. The composition of claim 8, which is administered to a subject, thereby promoting healing of bone to bone implants, bone to artificial implants, dental implants and bone grafts.

55. The composition of claim 8, which is administered to a subject or to the intestine of a subject, thereby increasing stem cells of the intestine.

56. The composition of claim 8, which is administered to a subject or the intestine of a subject, thereby increasing stem cells of the intestine and conferring resistance to toxic or lethal effects of exposure to radiation, or toxic, lethal or mucositis effects resulting from chemotherapy treatment.

57. The composition of claim 8, which is administered to a subject or the intestine of a subject, thereby conferring resistance to toxic or lethal effects of exposure to radiation, or toxic, lethal or mucositis effects resulting from chemotherapy treatment.

58. The composition of claim 8, which is administered to a subject or the intestine of a subject as a treatment for colitis, ulcerative colitis, or inflammatory bowel disease.

59. The composition of claim 8, which is administered to a subject to increase liver regeneration following liver surgery, following a liver donation, following a liver transplant, or following damage to the liver by a toxin.

60. The composition of claim 8, which is administered to a subject to promote recovery from or resistance to hepatotoxins, including acetaminophen and related compounds.

61. The composition of claim 8, which is administered to a subject to treat erectile dysfunction.

62. The composition of claim 8, administered to inhibit at least one of growth, proliferation, or metastasis of a 15-PGDH-expressing cancer.

63. A method of treating a subject in need of cell therapy comprising administering to the subject a therapeutically effective amount of a preparation comprising human hematopoietic stem cells administered the 15-PGDH inhibitor of claims 1-5 and/or a therapeutic composition comprising human hematopoietic stem cells and the 15-PGDH inhibitor of claims 1-5.

64. The method of claim 63, further comprising administering the 15-PGDH inhibitor of claims 1-5 to a subject who has received human hematopoietic stem cells and/or has received the preparation and/or the therapeutic composition.

65. The method of claim 64, wherein the subject has Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Chronic Lymphocytic Leukemia (CLL), juvenile myelomonocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, severe aplastic anemia, Fanconi's anemia, Paroxysmal Nocturnal Hemoglobinuria (PNH), pure red cell aplasia, megakaryocyte deficiency/congenital thrombocytopenia, severe combined immunodeficiency Syndrome (SCID), Wiskott-Aldrich syndrome, beta-thalassemia major, sickle cell anemia, Leehler's syndrome, adrenoleukodystrophy, metachromatic leukosis, myelodysplasia, refractory anemia, chronic myelomonocytic leukemia, Idiopathic myelometaplasia, familial erythrophagic lymphohistiocytosis, a solid tumor, a chronic granulomatous disease, mucopolysaccharidosis, or bubbly anemia.

66. A method of treating a subject having at least one symptom associated with ischemic tissue or ischemia damaged tissue comprising administering to the subject a therapeutically effective amount of a preparation comprising human hematopoietic stem cells administered the 15-PGDH inhibitor of claims 1-5 and/or a therapeutic composition comprising human hematopoietic stem cells and the 15-PGDH inhibitor of claims 1-5.

67. The method of claim 66, wherein the ischemia is associated with at least one of: acute coronary syndrome, Acute Lung Injury (ALI), Acute Myocardial Infarction (AMI), Acute Respiratory Distress Syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, cerebral edema, cerebral hypoperfusion, Burger's disease, burn, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced peripheral neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary heart disease (CAD), Critical Limb Ischemia (CLI), Crohn's disease, deep venous thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, cerebral ischemia, cerebral, Ischemia caused by diabetes, Disseminated Intravascular Coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic telangiectasia, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injury of the tendon, intermittent claudication, intestinal ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, placental ischemia, ischemic nephropathy, ischemic vascular disease, ischemia reperfusion injury, laceration, left trunk coronary heart disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, Peripheral Arterial Disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, precancerous, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, Retinopathy, sepsis, skin ulcers, solid organ transplantation, spinal cord injury, stroke, subchondral bone cysts, thrombosis, thrombotic cerebral ischemia, tissue ischemia, Transient Ischemic Attack (TIA), traumatic brain injury, ulcerative colitis, renovascular disease, vascular inflammatory disorders, retinal vascular neoplastic disease, and wounds to tissues or organs.

68. A method of increasing neutrophils in a subject in need thereof, the method comprising administering to the subject a 15-PGDH inhibitor according to claims 1-5.

69. The method of claim 68, further comprising administering a hematopoietic cytokine in combination with a 15-PGDH inhibitor.

70. A method of increasing the number of and/or mobilizing peripheral blood hematopoietic stem cells in a subject in need thereof, the method comprising administering to the subject the 15-PGDH inhibitor of claims 1-5.

71. The method of claim 70, further comprising administering G-CSF in combination with a 15-PGDH inhibitor.

72. the method of claim 70, further comprising administering a hematopoietic cytokine in combination with a 15-PGDH inhibitor.

73. The method of claim 70, further comprising administering plerixafor in combination with a 15-PGDH inhibitor.

74. The method of any one of claims 70 to 73, wherein peripheral blood hematopoietic stem cells are increased in number and/or mobilized for hematopoietic stem cell transplantation.

75. A method of increasing the number of hematopoietic stem cells in blood or bone marrow, the method comprising administering to the blood or bone marrow of the subject a 15-PGDH inhibitor according to claims 1-5.

76. The method of claim 75, further comprising administering G-CSF in combination with a 15-PGDH inhibitor.

77. The method of claim 75, further comprising administering a hematopoietic cytokine in combination with a 15-PGDH inhibitor.

78. The method of claim 75, further comprising administering plerixafor in combination with a 15-PGDH inhibitor.

79. A method of treating or preventing a fibrotic disease, disorder or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the 15-PGDH inhibitor according to claims 1-5.

80. The method of claim 79, wherein said fibrotic disease, disorder or condition is characterized in whole or in part by overproduction of fibrotic material, including overproduction of fibrotic material within extracellular matrix, or replacement of normal tissue elements by aberrant, nonfunctional and/or excessively accumulated matrix-associated components.

81. the method of claim 79, wherein the fibrotic disease, disorder or condition is selected from the group consisting of systemic sclerosis, multifocal fibrosis, renal systemic fibrosis, scleroderma, graft-versus-host disease of scleroderma, renal fibrosis, glomerulosclerosis, tubulointerstitial fibrosis, progressive or diabetic nephropathy, cardiac fibrosis, pulmonary fibrosis, glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, chemotherapy/radiotherapy-induced pulmonary fibrosis, oral fibrosis, myocardial endocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, necrotizing fasciitis, eosinophilic fasciitis, general fibrosis syndrome characterized by different degrees of replacement of normal muscle tissue by fibrous tissue, retroperitoneal fibrosis, and the like, Liver fibrosis, cirrhosis, chronic renal failure, myelofibrosis, drug-induced ergotoxism, glioblastoma in the plum-fomeni syndrome, sporadic glioblastoma, myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative syndrome, gynecological tumors, kaposi's sarcoma, hansen's disease, collagenous colitis, acute fibrosis and specific organ fibrosis.

82. The method of claim 79, wherein said fibrotic disease, disorder or condition comprises pulmonary fibrosis.

83. The method of claim 82, wherein the pulmonary fibrosis is selected from the group consisting of pulmonary fibrosis, pulmonary hypertension, Chronic Obstructive Pulmonary Disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal mineworker's pneumoconiosis, charcoal pneumoconiosis, hypersensitivity pneumonitis, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by infectious agents, pulmonary fibrosis caused by inhalation of toxic gases, aerosols, chemical dusts, smoke or vapors, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof.

84. The method of claim 82, wherein said pulmonary fibrosis is cystic fibrosis.

85. The method of claim 79, wherein said fibrotic disease, disorder or condition comprises renal fibrosis.

86. The method of claim 79, wherein said fibrotic disease, disorder or condition comprises liver fibrosis.

87. The method of claim 86, wherein said liver fibrosis is caused by: chronic liver disease, viral cirrhosis, hepatitis b virus infection, hepatitis c virus infection, hepatitis d virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic or non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis obesity, diabetes, protein malnutrition, coronary heart disease, autoimmune hepatitis, cystic fibrosis, alpha-1-antitrypsin deficiency, primary biliary cirrhosis, drug reaction and exposure to toxins, or a combination thereof.

88. The method of claim 79, wherein said fibrotic disease, disorder or condition comprises cardiac fibrosis.

89. The method of claim 79, wherein said fibrotic disease, disorder or condition comprises systemic sclerosis.

90. The method of claim 79, wherein the fibrotic disease, disorder or condition is caused by post-surgical adhesion formation.

91. the method of claim 79, wherein the 15-PGDH inhibitor is administered in an amount effective to reduce or inhibit collagen deposition, inflammatory cytokine expression and/or inflammatory cytokine infiltration in a tissue or organ of the subject to be treated.

92. A method of promoting neuroprotection from axonal degeneration, neuronal cell death and/or glial cell injury following injury, enhancing neuronal signaling for learning and memory, stimulating neuronal regeneration following injury, and/or treating a disease, disorder and/or condition of the nervous system in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the 15-PGDH inhibitor of claims 1-5.

93. The method of claim 92, wherein the disease, disorder and/or condition of the nervous system comprises at least one of a neurological disorder, neuropsychiatric disorder, a neurological injury, a neurotoxic disorder, neuropathic pain and a neurodegenerative disorder.

94. The method of claim 92, wherein the neurological disorder comprises at least one of traumatic or toxic injury to the peripheral or cranial nerves, the spinal cord, or to the brain, cranial nerves, traumatic brain injury, stroke, cerebral aneurysm, and spinal cord injury; the neurological disorder may also include at least one of alzheimer's disease, dementia associated with alzheimer's disease, parkinson's disease, diffuse body disease of the lewy body, senile dementia, huntington's chorea, gilles de la tourette's syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy, or jacobia-creutzfeldt-jakob disease.

95. The method of claim 92, wherein the nerve damage is caused by or associated with at least one of: epilepsy, cerebrovascular disorders, autoimmune diseases, sleep disorders, autonomic nervous disorders, bladder disorders, abnormal metabolic states, disorders of the muscular system, infectious and parasitic diseases, endocrine diseases, nutritional and metabolic diseases, immune diseases, diseases of the blood and blood forming organs, mental disorders, diseases of the nervous system, diseases of the sensory organs, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the urogenital system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal and connective tissue, congenital abnormalities or conditions of perinatal origin.

96. The method of claim 92, wherein the 15-PGDH inhibitor is administered in an amount effective to stimulate hippocampal neurogenesis, thereby treating neuropsychiatric and neurodegenerative diseases, including schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, parkinson's disease, alzheimer's disease, down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, huntington's chorea, stroke, radiotherapy, chronic stress, and abuse of neuro-active drugs, such as alcohol, opioids, methamphetamine, phencyclidine, and ***e.

Background

Short Chain Dehydrogenases (SCDs) are a family of dehydrogenases that have only 15% to 30% sequence identity and similarity mainly in the coenzyme-binding and substrate-binding domains. In addition to their role in ethanol detoxification, SCD are also involved in the synthesis and degradation of fatty acids, steroids and some prostaglandins, and thus are implicated in a variety of disorders, such as lipid storage diseases, myopathies, SCD defects and certain genetic diseases.

SCD, 15-hydroxy-prostaglandin dehydrogenase (15-PGDH), (hydroxy prostaglandin dehydrogenase 15- (nicotinamide adenine dinucleotide); 15-PGDH; enzyme Commission number 1.1.1.141; encoded by the HPGD gene), is representative of the activity of various prostaglandins, leukotrienes, and hydroxyeicosatetraenoic acids (HETEs) (e.g., by catalyzing PGE₂Oxidation to 15-keto-prostaglandin E2, 15 k-PGE). The human enzyme is encoded by the HPGD gene and consists of a homodimer with a subunit size of 29 kDa. The enzyme belongs to the evolutionarily conserved short-chain dehydrogenase/reductase (SDR) superfamily and is referred to as SDR36C1 according to the recently approved systematic nomenclature of human enzymes. To date, 2 forms of 15-PGDH enzyme activity have been identified, each of which encodes the HPGD geneCodogenic NAD + -dependent type I15-PGDH, and type II NADP-dependent type 15-PGDH also known as carbonyl reductase 1(CBR1, SDR21C 1). However, the preference of CBR1 for NADP and the high Km value of CBR1 for most prostaglandins suggests that most in vivo activities can be attributed to type I15-PGDH encoded by the HPGD gene, hereafter and throughout the text, both abbreviated as 15-PGDH.

Recent studies have shown that inhibitors of 15-PGDH may be of therapeutic value. Recent studies have suggested that the expression of 15-PGDH is increased in the protection of thrombin-mediated cell death. It is known that 15-PGDH pairs prostaglandin E2 (PGE)₂) Is responsible for the inactivation of the prostaglandin E2 (PGE)₂) Is a downstream product of COX-2 metabolism. PGE₂Have been shown to be advantageous in a variety of biological processes, such as hair density, skin wound healing and bone formation. Recent work has shown that inhibitors of 15-PGDH promote tissue regeneration and wound healing in multiple tissues.

Summary of The Invention

The embodiments described herein relate to compounds and methods for modulating Short Chain Dehydrogenase (SCD) (e.g., 15-PGDH) activity, modulating tissue prostaglandin levels, and/or treating diseases, disorders, or conditions requiring modulation of SCD (e.g., 15-PGDH) activity and/or prostaglandin levels.

In some embodiments, the modulator of SCD may be an SCD inhibitor, which may be administered to a tissue or blood of a subject in an amount effective to inhibit SCD enzyme activity. The SCD inhibitor may be a 15-PGDH inhibitor, which may be administered to a tissue or blood of a subject in an amount effective to increase the level of prostaglandins in the tissue or blood. The 15-PGDH inhibitor may comprise a compound having at least one of the following formulae:

Wherein X¹Is N or CR⁴；

X²Is S, S ═ O, S (═ O)₂Or C ═ O;

X³Is CR⁸(the compound formed has 10Polycyclic heteroaryl of ring atoms) or absent (the compound forms a polycyclic heteroaryl having 9 ring atoms);

X⁴Is N, NH or CR⁷；

X⁵Is N, C ═ O or CR¹⁶(ii) a And if X⁴Is CR⁷Or X³is absent, X⁵is N; if X is⁵Is C ═ O, X⁴Is NH; and if X⁴Is N and X³Is CR⁸，X⁵Is CR¹⁶；

R¹、R²、R³、R⁴、R⁹、R¹⁰And R¹⁶Are the same or different and are independently selected from the group consisting of hydrogen, oxygen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₀Aryl, heterocycloalkenyl containing 5-7 ring atoms (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of the ring atoms are independently selected from N, NH, N (C)₁-C₃Alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀Aryloxy, acyl (including C)₂-C₂₄Alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO)^-) Carbamoyl (- (CO) -NH)₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄Alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄Alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂Alkyl), C₅-C₂₀Arylsulfonyl (-SO)₂-aryl), aminosulfonyl (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH2)_nO]_m) Phosphate, phosphoric acidEster [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]groups comprising amino acids or other moieties predicted to carry a positive or negative charge at physiological pH, and combinations thereof;

And pharmaceutically acceptable salts thereof.

In some embodiments, R²Or R³Is not H, and R⁹Or R¹⁰Is not H.

In some embodiments, the 15-PGDH inhibitor may have an IC of less than 1 μ M at recombinant 15-PGDH concentrations of about 5nM to about 10nM₅₀Or preferably less than 250nM IC₅₀Or more preferably less than 50nM₅₀Or more preferably less than 10nM IC₅₀Or more preferably less than 5nM IC₅₀Inhibiting the enzymatic activity of recombinant 15-PGDH.

The 15-PGDH inhibitor may be provided as a topical composition, wherein the composition may be administered to the skin of a subject, thereby promoting and/or stimulating pigmentation and/or hair growth of the skin and/or inhibiting hair loss and/or treating skin damage or inflammation.

The 15-PGDH inhibitor may also be administered to a subject to promote wound healing, tissue repair and/or tissue regeneration and/or implantation or regeneration of a tissue graft.

In one embodiment, the 15-PGDH inhibitor may be administered to a subject to treat at least one of oral ulcers, gum disease, colitis, ulcerative colitis, gastroduodenal ulcers, inflammatory bowel disease, vascular insufficiency, Raynaud's disease, Buerger's disease, diabetic neuropathy, pulmonary hypertension, cardiovascular disease, and renal disease.

In another embodiment, the 15-PGDH inhibitor may be administered to a subject in combination with a prostanoid agonist for the purpose of enhancing the therapeutic effect of the agonist in prostanoid response disorders (prostaglandin responsiveness conditions).

In other embodiments, the 15-PGDH inhibitor may be administered to a subject and/or a tissue of a subject, thereby increasing tissue stem cells. For example, the 15-PGDH inhibitor may be administered to bone marrow of a subject, thereby increasing stem cells in the subject.

In other embodiments, the 15-PGDH inhibitor may be administered to a tissue graft donor, a bone marrow graft donor, and/or a hematopoietic stem cell donor, and/or a tissue graft, and/or a bone marrow graft, and/or a hematopoietic stem cell graft, thereby increasing the fitness of the donor tissue graft, the donor bone marrow graft, and/or the donor hematopoietic stem cell graft. For example, the 15-PGDH inhibitor may be administered to a subject and/or bone marrow of a subject, thereby increasing the fitness of the bone marrow as a donor graft; and/or administering to the subject a preparation of hematopoietic stem cells, thereby increasing the fitness of the stem cell preparation as a donor graft; and/or administering to the subject a preparation of peripheral blood hematopoietic stem cells, thereby increasing the fitness of the stem cell preparation as a donor graft; and/or administering to a preparation of cord blood stem cells, thereby increasing the fitness of the stem cell preparation as a donor graft; and/or to a preparation of cord blood stem cells, thereby reducing the number of units of cord blood required for transplantation.

In other embodiments, the 15-PGDH inhibitor may be administered to a subject, thereby reducing rejection of tissue transplants, enhancing implantation of tissue and/or bone marrow transplants (e.g., after treatment of the subject or bone marrow of the subject with radiation therapy, chemotherapy, or immunosuppressive therapy); enhancing engraftment of a progenitor cell graft, hematopoietic stem cell graft, or cord blood stem cell graft, enhancing engraftment of a hematopoietic stem cell graft or cord blood stem cell graft (e.g., after treatment of the subject or bone marrow of the subject with radiation therapy, chemotherapy, or immunosuppressive therapy); and/or reducing the number of units of cord blood required for transplantation into a subject.

In other embodiments, the 15-PGDH inhibitor may be administered to a recipient of a tissue graft transplant, a bone marrow graft transplant, and/or a hematopoietic stem cell transplant or a cord blood stem cell transplant, thereby reducing the administration of other therapies or growth factors.

In some embodiments, the 15-PGDH inhibitor may be administered to a subject or a tissue graft of a subject, thereby reducing graft rejection, enhancing graft implantation, and/or enhancing graft implantation (e.g., after treatment of the subject or bone marrow of the subject with radiation therapy, chemotherapy, or immunosuppressive therapy).

In other embodiments, the 15-PGDH inhibitor may be administered to a subject or bone marrow of a subject, thereby conferring resistance to toxic or lethal effects of exposure to radiation, to cyclophosphamide, fludarabine, chemotherapy, or immunosuppressive therapy, thereby reducing radiation-induced pulmonary toxicity, and/or reducing infection.

In other embodiments, the 15-PGDH inhibitor may be administered to a subject, thereby increasing the number of neutrophils after hematopoietic cell transplantation using bone marrow, hematopoietic stem cells, or umbilical cord blood; increasing the number of neutrophils in the neutropenic subject following chemotherapy administration or radiation therapy; increasing the number of neutrophils in a subject with aplastic anemia, myelodysplasia, myelofibrosis, neutropenia from other bone marrow diseases, drug-induced neutropenia, autoimmune neutropenia, idiopathic neutropenia, or neutropenia following viral infection; increasing the number of neutrophils in the neutropenic subject; increasing the number of platelets following hematopoietic cell transplantation of bone marrow, hematopoietic stem cells or umbilical cord blood; increasing platelet number in a thrombocytopenic subject following chemotherapy administration or radiation therapy; increasing the number of platelets in a subject with aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia due to other bone marrow diseases, drug-induced thrombocytopenia, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia, or thrombocytopenia following viral infection; increasing platelet count in a thrombocytopenic subject; increasing the number of blood cells, or the hematocrit or hemoglobin level, after hematopoietic cell transplantation of bone marrow, hematopoietic stem cells or umbilical cord blood; increasing the blood cell count, or hematocrit or hemoglobin level, of a subject with anemia following chemotherapy administration or radiation therapy; increasing the hematocrit or hemoglobin count of a subject having aplastic anemia, myelodysplasia, myelofibrosis, anemia due to other disorders of the bone marrow, drug-induced anemia, immune-mediated anemia, anemia from chronic diseases, anemia after viral infection, or anemia of unknown cause; increasing the blood cell count, or red blood cell ratio or hemoglobin level, of a subject with anemia; increasing bone marrow stem cells after hematopoietic cell transplantation of bone marrow, hematopoietic stem cells or umbilical cord blood; increasing bone marrow stem cells in the subject following chemotherapy administration or radiation therapy; and/or increasing bone marrow stem cells in a subject with aplastic anemia, myelodysplasia, myelofibrosis, other disorders of bone marrow, drug-induced cytopenia, immunocytopenia, cytopenia after viral infection, or cytopenia.

In other embodiments, administration of a 15-PGDH inhibitor can be used to modulate hematopoietic stem cells and hematopoiesis. For 15-PGDH inhibitors, they can be administered alone or in combination with cytokines to a subject in need thereof, thereby increasing and/or mobilizing hematopoietic stem cells and/or neutrophils in the blood, bone marrow, and/or tissues of the subject.

In some embodiments, administration of a 15-PGDH inhibitor may be combined with G-CSF for the purpose of increasing neutrophils.

In other embodiments, administration of the 15-PGDH inhibitor may be combined with a hematopoietic cytokine, with the aim of increasing neutrophils.

In other embodiments, administration of the 15-PGDH inhibitor may be combined with G-CSF for the purpose of increasing the number of and/or mobilizing peripheral blood hematopoietic stem cells.

In other embodiments, administration of the 15-PGDH inhibitor may be combined with a hematopoietic cytokine for the purpose of increasing the number of and/or mobilizing peripheral blood hematopoietic stem cells.

In some embodiments, administration of the 15-PGDH inhibitor may be combined with a second agent, including Plerixafor, for the purpose of increasing the number of and/or mobilizing peripheral blood hematopoietic stem cells.

In other embodiments, administration of the 15-PGDH inhibitor may be combined with G-CSF with the aim of increasing the number of and/or mobilizing peripheral blood hematopoietic stem cells for hematopoietic stem cell transplantation.

In other embodiments, the administration of the 15-PGDH inhibitor may be combined with a hematopoietic cytokine for the purpose of increasing the number of and/or mobilizing peripheral blood hematopoietic stem cells for hematopoietic stem cell transplantation.

in other embodiments, the administration of the 15-PGDH inhibitor may be combined with a second agent (including plerixafor) for the purpose of increasing the number of and/or mobilizing peripheral blood hematopoietic stem cells for hematopoietic stem cell transplantation.

in other embodiments, administration of the 15-PGDH inhibitor may be combined with G-CSF for the purpose of increasing the number of hematopoietic stem cells in the blood or bone marrow.

In other embodiments, administration of the 15-PGDH inhibitor may be combined with a hematopoietic cytokine, with the aim of increasing the number of hematopoietic stem cells in the blood or bone marrow.

In other embodiments, the 15-PGDH inhibitor may be administered to a recipient of a tissue graft transplant, bone marrow transplant, and/or hematopoietic stem cell transplant, or a recipient of an umbilical cord blood stem cell transplant, to reduce administration of other therapies or growth factors.

In other embodiments, the 15-PGDH inhibitor may be administered to a subject, thereby increasing the response to a cytokine in the presence of a cytopenia, wherein the cytopenia includes any one of: neutropenia, thrombocytopenia, lymphopenia and anemia; and the cytokine has an increased response enhanced by a 15-PGDH inhibitor, the inhibitor comprising any one of: G-CSF, GM-CSF, EPO, IL-3, IL-6, TPO-RA (thrombopoietin receptor agonist) and SCF.

In some embodiments, the 15-PGDH inhibitor may be administered to a subject, thereby increasing bone density, treating osteoporosis, promoting fracture healing, or promoting healing after skeletal surgery or joint replacement, and/or promoting healing of bones and bone implants, bones and artificial implants, dental implants, and bone grafts.

In other embodiments, the 15-PGDH inhibitor may be administered to a subject or to the intestine of a subject, thereby increasing stem cell or cell proliferation in the intestine, and/or conferring resistance to toxic or lethal effects of exposure to radiation, or to toxic, lethal or mucositis effects resulting from chemotherapy treatment.

in some embodiments, the 15-PGDH inhibitor may be administered to a subject or to the intestine of a subject as a treatment for colitis, ulcerative colitis, or inflammatory bowel disease.

In other embodiments, the 15-PGDH inhibitor may be administered to a subject, thereby increasing liver regeneration after liver surgery, after a liver donation, after a liver transplant, or after the liver is damaged by a toxin; and/or to promote recovery from or resistance to hepatotoxins, including acetaminophen and related compounds.

In other embodiments, the 15-PGDH inhibitor may be administered to a subject, thereby treating erectile dysfunction.

In other embodiments, the 15-PGDH inhibitor may be administered, thereby inhibiting at least one of growth, proliferation, or metastasis of a cancer that expresses 15-PGDH.

Other embodiments described herein relate to a method of treating a subject in need of cell therapy. The method comprises administering to a subject a therapeutically effective amount of a preparation comprising human hematopoietic stem cells administered a 15-PGDH inhibitor described herein and/or a therapeutic composition comprising human hematopoietic stem cells and a 15-PGDH inhibitor described herein.

in some embodiments, the subject has received human hematopoietic stem cells, and/or has received the preparation and/or therapeutic composition.

in other embodiments, the subject has Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Myeloid Leukemia (CML), Chronic Lymphocytic Leukemia (CLL), juvenile myelomonocytic leukemia, hodgkin's lymphoma, non-hodgkin's lymphoma, multiple myeloma, severe aplastic anemia, Fanconi's anemia (Fanconi's anemia), Paroxysmal Nocturnal Hemoglobinuria (PNH), pure red cell aplasia, megakaryocytopenia/congenital thrombocytopenia, severe combined immunodeficiency Syndrome (SCID), Wiskott-Aldrich syndrome, β -severe thalassemia, sickle cell anemia, Hurler's syndrome, adrenoleukodystrophy, metachromatic leukosis, myelodysplasia, and myelodysplasia, Refractory anemia, chronic myelomonocytic leukemia, idiopathic myelometaplasia, familial erythrophagic lymphohistiocytosis, solid tumors, chronic granulomatous diseases, mucopolysaccharidoses, or barrennes anemia (diamondblankfan anemia).

Other embodiments relate to a method of treating a subject having at least one symptom associated with an ischemic tissue or tissue damaged by ischemia. The method comprises administering to a subject a therapeutically effective amount of a preparation comprising human hematopoietic stem cells administered a 15-PGDH inhibitor described herein and/or a therapeutic composition comprising human hematopoietic stem cells and a 15-PGDH inhibitor described herein.

In some embodiments, the ischemia may be associated with at least one of: acute coronary syndrome, Acute Lung Injury (ALI), Acute Myocardial Infarction (AMI), Acute Respiratory Distress Syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, cerebral edema, cerebral hypoperfusion, Burger's disease, burn, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced peripheral neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary heart disease (CAD), Critical Limb Ischemia (CLI), Crohn's disease, deep venous thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, Ischemia caused by diabetes, Disseminated Intravascular Coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic telangiectasia, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injury of the tendon, intermittent claudication, intestinal ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, placental ischemia, ischemic nephropathy, ischemic vascular disease, ischemia reperfusion injury, laceration, left trunk coronary heart disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, Peripheral Arterial Disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, precancerous, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, Retinal ischemia, retinopathy, sepsis, skin ulcers, solid organ transplantation, spinal cord injury, stroke, subchondral bone cysts, thrombosis, thrombotic cerebral ischemia, tissue ischemia, Transient Ischemic Attack (TIA), traumatic brain injury, ulcerative colitis, renal angiopathy, vascular inflammatory disorders, retinal vascular disease (von Hippel-Lindau syndrome), and wounds of tissues or organs.

Other embodiments relate to methods of treating and/or preventing fibrosis and various fibrotic diseases, disorders or conditions by administering a 15-PGDH inhibitor. In some embodiments, a 15-PGDH inhibitor described herein can be administered to a subject in need thereof, thereby reducing fibrotic symptoms, such as collagen deposition, inflammatory cytokine expression, and inflammatory cell infiltration; and the treatment and/or prevention of a variety of fibrotic diseases, disorders and conditions, all or part of which are characterized by overproduction of fibrotic material, including overproduction of fibrotic material within extracellular matrix, or replacement of normal tissue elements by abnormal, nonfunctional and/or excessive accumulated matrix-related components.

The fibrotic disease, disorder or condition characterized in whole or in part by overproduction of fibrotic material may include systemic sclerosis, multifocal fibrosclerosis, renal systemic fibrosis, scleroderma (including scleroderma, generalized scleroderma or linear scleroderma), graft-versus-host disease of scleroderma, renal fibrosis (including glomerulosclerosis, tubulointerstitial fibrosis, progressive renal disease or diabetic nephropathy), cardiac fibrosis (e.g., cardiac fibrosis), pulmonary fibrosis (e.g., pulmonary fibrosis, glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrosis lung disease, interstitial lung disease, and chemotherapy/radiotherapy-induced pulmonary fibrosis), oral fibrosis, myocardial endocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, crohn's disease, necrotizing fasciitis, inflammation of the skin, inflammatory bowel disease, or inflammatory bowel disease, Eosinophilic fasciitis, general fibrosis syndrome (characterized by replacement of normal muscle tissue by fibrous tissue to varying degrees), retroperitoneal fibrosis, pulmonary fibrosis, chronic interstitial hepatitis, chronic renal failure, myelofibrosis (myelofibrosis), drug-induced ergotoxemia, glioblastoma in Li-fluminella syndrome (Li-fraumenison), sporadic glioblastoma, myelogenous leukemia, acute myelogenous leukemia, myelodysplastic syndrome, myeloproliferative syndrome, gynecological tumors, Kaposi's sarcoma, hanseng's disease, collagenous colitis, acute fibrosis, and specific organ fibrosis, among others.

In some embodiments, a method of treating or preventing a fibrotic disease, disorder or condition comprises administering to a subject in need thereof a therapeutically effective amount of a 15-PGDH inhibitor.

In some embodiments, the 15-PGDH inhibitor is useful for treating or preventing pulmonary fibrosis. Pulmonary fibrosis that can be treated can be selected from the group consisting of pulmonary fibrosis, pulmonary hypertension, Chronic Obstructive Pulmonary Disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal mineworker's pneumoconiosis, charcoal pneumoconiosis, hypersensitivity pneumonitis, pulmonary fibrosis resulting from inhalation of inorganic dust, pulmonary fibrosis resulting from infectious agents, pulmonary fibrosis resulting from inhalation of toxic gases, aerosols, chemical dusts, smoke or vapors, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof.

In other embodiments, the 15-PGDH inhibitor is useful for treating or preventing renal fibrosis. The renal fibrosis may result from dialysis following renal failure, catheter placement, renal disease, glomerulosclerosis, glomerulonephritis, chronic renal insufficiency, acute renal injury, end stage renal disease or failure, or a combination thereof.

In other embodiments, the 15-PGDH inhibitor is useful for treating or preventing liver fibrosis. The hepatic fibrosis may be caused by chronic liver disease, viral cirrhosis, hepatitis b virus infection, hepatitis c virus infection, hepatitis d virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis obesity, diabetes, protein malnutrition, coronary heart disease, autoimmune hepatitis, cystic fibrosis, alpha-1-antitrypsin deficiency, primary biliary cirrhosis, drug reactions and exposure to toxins, or a combination thereof.

In some embodiments, the 15-PGDH inhibitor is useful for treating or preventing cardiac fibrosis, such as cardiac fibrosis and myocardial endocardial fibrosis.

In some embodiments, the 15-PGDH inhibitor is useful for treating or preventing systemic sclerosis.

In some embodiments, the 15-PGDH inhibitor is useful for treating or preventing a fibrotic disease, disorder or condition resulting from post-surgical adhesion formation.

In some embodiments, the 15-PGDH inhibitor can be used to reduce or prevent scar formation in a subject.

In other embodiments, the 15-PGDH inhibitor can be used to reduce or prevent scar formation or scleroderma on the skin.

In various embodiments, the 15-PGDH inhibitor may be administered in a therapeutically effective amount such that at least one symptom or feature of the fibrotic disease, disorder or condition, or other related disease, disorder or condition, is reduced in intensity, severity, or frequency, or has delayed onset.

In other embodiments, the 15-PGDH inhibitor may be used in a method of reducing or decreasing collagen secretion or collagen deposition in a tissue or organ (e.g., lung, liver, intestine, colon, skin, or heart) of a subject. The method can comprise administering to a subject in need thereof a therapeutically effective amount of a 15-PGDH inhibitor. The subject may have or be at risk of excessive collagen secretion or collagen deposition in a tissue or organ (e.g., kidney, lung, liver, intestine, colon, skin, or heart). Usually, excessive collagen secretion or collagen deposition in organs is caused by injury or damage. Such damage or impairment may be organ specific. The 15-PGDH inhibitor may be administered for a sufficient period of time to completely or partially reduce or reduce the level of collagen deposition in a tissue or organ. A sufficient period of time may be 1 week, or 1 week to 1 month, or 1 month to 2 months, or 2 months or longer. For chronic conditions, the 15-PGDH inhibitor may advantageously be administered for life.

in other embodiments, the 15-PGDH inhibitors described herein can promote neuroprotection from axonal degeneration following injury, neuronal cell death and/or glial cell injury, enhance neuronal signaling for learning and memory, stimulate neuronal regeneration following injury, and/or treat diseases, disorders, and/or conditions of the nervous system in a subject.

in some embodiments, a disease, disorder, and/or condition of the nervous system that can be treated with the 15-PGDH inhibitor can include at least one of a neurological disorder, a neuropsychiatric disorder, a nerve injury, a neurotoxic disorder, neuropathic pain, and a neurodegenerative disorder.

For example, the neurological disorder may include at least one of traumatic or toxic injury to the peripheral or cranial nerve, the spinal cord or to the brain, cranial nerve, traumatic brain injury, stroke, cerebral aneurysm, and spinal cord injury. The neurological disorder may further include at least one of Alzheimer's disease, dementia associated with Alzheimer's disease, Parkinson's disease, diffuse body disease (Lewy diffuse body diseases), senile dementia, huntington's disease, gillington's disease, Gilles de la tourette's syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy or Jakob-creutzfeldt disease.

In some embodiments, the nerve damage may be caused by or associated with at least one of: epilepsy, cerebrovascular disorders, autoimmune diseases, sleep disorders, autonomic disorders, bladder disorders, abnormal metabolic states, disorders of the muscular system, infectious and parasitic diseases, endocrine disorders, nutritional and metabolic diseases, immune disorders, diseases of the blood and blood-forming organs, mental disorders, diseases of the nervous system, diseases of the sensory system, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the urogenital system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, congenital abnormalities or disorders of perinatal origin.

In certain embodiments, the 15-PGDH inhibitor may be administered to a subject or to a neuron in a subject to promote survival, growth, development, and/or function of the neuron. In certain embodiments, the 15-PGDH inhibitors are useful for stimulating hippocampal neurogenesis, for treating neuropsychiatric and neurodegenerative diseases, including schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, parkinson's disease, alzheimer's disease, down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, huntington's chorea, stroke, radiotherapy, chronic stress, and abuse of neuroactive drugs, such as alcohol, opioids, methamphetamine, phencyclidine, and ***e.

Detailed Description

For convenience, certain terms used in the specification, examples, and appended claims are collected here. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" refers to one element or more than one element.

the terms "comprising", "including", "having" and "having" are used in an inclusive, open sense, in which additional elements may be included. As used herein, terms such as, for example, are non-limiting and are for illustrative purposes only. "include" and "include but are not limited to" are used interchangeably.

As used herein, the term "or" should be understood to mean "and/or" unless the context clearly dictates otherwise.

As used herein, the term "about" or "approximately" means that the amount, level, value, quantity, frequency, percentage, dimension, size, amount, weight, or length may vary by as much as 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% relative to a reference amount, level, value, amount, frequency, percentage, dimension, size, amount, weight, or length. In one embodiment, the term "about" or "approximately" refers to a range of a quantitative, horizontal, value, quantity, frequency, percentage, dimension, size, quantity, weight, or length that is ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, or ± 1% relative to a reference quantitative, horizontal, value, quantity, frequency, percentage, dimension, size, quantity, weight, or length.

It should be noted that the structures of some of the compounds of the present application include asymmetric (chiral) carbon or sulfur atoms. Thus, it is to be understood that isomers formed by such asymmetry are encompassed by the present invention unless otherwise indicated. Such isomers may be obtained in substantially pure form by conventional separation techniques and by stereochemically controlled synthetic methods. The compounds of the present application may exist as stereoisomers and thus may be produced as single stereoisomers or as mixtures.

The term "isomeric" refers to compounds having the same molecular formula, but differing in nature or in the order of incorporation of the atoms or the spatial arrangement of the atoms. Isomers in which the atoms differ in their spatial arrangement are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers", while stereoisomers that are not overlapping mirror images are referred to as "enantiomers", or sometimes optical isomers. Carbon atoms bonded to 4 non-identical substituents are referred to as "chiral centers", while sulfur (e.g., sulfoxide or sulfenamide) bonded to 3 or 4 different substituents are also referred to as "chiral centers".

The term "chiral isomer" refers to a compound having at least one chiral center. It has 2 opposite chiral enantiomeric forms and can exist as a single enantiomer or as a mixture of enantiomers. Mixtures of single enantiomeric forms containing equal amounts of opposite chirality are referred to as "racemic mixtures". Compounds with more than one chiral center have 2n-1 enantiomeric pairs, where n is the number of chiral centers. Compounds having more than one chiral center may exist as a single diastereomer or as a mixture of diastereomers, referred to as "mixtures of diastereomers". When a chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of the chiral center. Alternatively, when one or more chiral centers are present, a stereoisomer may be characterized as (+) or (-). Absolute configuration refers to the spatial arrangement of substituents attached to a chiral center. The substituents considered to be attached to the chiral center are ordered according to the Cahn-Ingold-Prelog order rule (Cahn et al, Angew. chem. Inter. Edit.1966,5,385; errata 511; Cahn et al, Angew. chem.1966,78,413; Cahn and Ingold, J chem. Soc.1951(London), 612; Cahn et al, Experienta 1956,12, 81; Cahn, J.chem. Educ.1964,41,116).

the term "geometric isomer" refers to a diastereomer, the presence of which is due to a hindered rotation about a double bond. These configurations are distinguished by the prefixes cis (cis) and trans (trans), or Z and E in the name, which indicates that the groups are on the same side or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rule. In addition, the structures and other compounds discussed in this application contain all of their inverted isomers.

The term "inverted isomer" is a type of stereoisomer in which the atoms of the 2 isomers differ in their spatial arrangement. The presence of the inverted isomer is due to the restricted rotation of the larger group due to the hindered rotation about the central bond. Such inverted isomers usually exist in the form of a mixture, but due to recent development of chromatographic techniques, it has been possible to separate a mixture of 2 inverted isomers in some cases.

The term "crystalline polymorph" or "crystalline form" refers to a crystal structure in which a compound (or a salt or solvate thereof) can be crystallized in different crystal packing arrangements, wherein all arrangements have the same elemental composition. Different crystalline forms typically have different X-ray diffraction pattern spectra, infrared spectra, melting points, density hardness, crystalline form, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystal form to dominate. Crystalline forms of the compounds may be prepared by crystallization under different conditions.

The term "derivative" refers to a compound having a common core structure and substituted with a variety of groups, as described herein.

The term "bioisostere" refers to a compound resulting from the interchange of one atom or group of atoms with another substantially similar atom or group of atoms. The purpose of bioisosteric replacement is to create new compounds with similar biological properties as the parent compound. Bioisosteric replacements may be physicochemical-based or topologically-based. Examples of carboxylic acid bioisosteres include acyl sulfonimides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, chem.Rev.96,3147-3176 (1996).

The phrases "parenteral administration" and "administered parenterally" are art-recognized terms and include modes of administration other than enteral and topical administration, such as injection, and include, but are not limited to, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

The term "treating" is art-recognized and includes inhibiting a disease, disorder or condition in a subject, e.g., arresting its progression; and alleviating the disease, disorder or condition, e.g., regression (regression) of the disease, disorder and/or condition. Treating a disease or disorder includes alleviating at least one symptom of the particular disease or disorder, even if the underlying pathophysiology is unaffected (Not affected).

The term "preventing" is art-recognized and includes preventing a disease, disorder, or condition from occurring in a subject, wherein the subject may be predisposed to the disease, disorder, and/or condition, but has not yet been diagnosed as having the disease, disorder, and/or condition. Preventing a condition associated with a disease includes preventing the occurrence of the condition after the disease is diagnosed but before the condition is diagnosed.

The term "pharmaceutical composition" refers to a formulation comprising a disclosed compound in a form suitable for administration to a subject. In a preferred embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is in any of a variety of forms including, for example, a capsule, an IV bag, a tablet, a unidirectional flow pump on aerosol, or a vial. In a unit dose of the composition, the amount of active ingredient (e.g., a formulation of the disclosed compound or salt thereof) is an effective amount and will vary with the particular treatment involved. Those skilled in the art will appreciate that routine variations in dosage are sometimes required depending on the age and condition of the patient. The dosage may also depend on the route of administration. Various routes are contemplated, including oral, intrapulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, inhalation, and the like. Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, aerosolized compounds, and inhalants. In a preferred embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

The term "flash dose" refers to a formulation of a compound in a fast-dispersing dosage form.

The term "immediate release" is defined as the release of the compound from the dosage form in a relatively short period of time, typically up to about 60 minutes. The term "modified release" is defined to include delayed release, extended release and pulsatile release. The term "pulsed release" is defined as the series of releases of a drug product from a dosage form. The term "sustained release" or "extended release" is defined as the continuous release of a compound from a dosage form over an extended period of time.

The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the terms include compositions, polymers, and other materials and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically acceptable carrier" is art-recognized and includes, for example, a pharmaceutically acceptable substance, composition, or vehicle (e.g., a liquid or solid filler, diluent, excipient, solvent, or encapsulating substance) for carrying or transporting any subject composition from one organ or portion of the body to another organ or portion of the body. Various carriers must be "acceptable" in the sense of being compatible with the other components of the subject composition and not injurious to the patient. In certain embodiments, the pharmaceutically acceptable carrier is pyrogen-free. Some examples of substances that may serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelling; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cotton oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) ethylene glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) physiological saline; (18) ringer solution; (19) ethanol; (20) a phosphate buffer solution; and (21) other non-toxic compatible materials used in pharmaceutical formulations.

The compounds of the present application are capable of further salt formation. All of these forms are also contemplated within the scope of the present invention.

"pharmaceutically acceptable salts" of a compound refer to salts that are pharmaceutically acceptable and have the desired pharmaceutical activity of the parent compound. For example, the salts may be acid addition salts. One embodiment of an acid addition salt is the hydrochloride salt. Pharmaceutically acceptable salts can be synthesized by conventional chemical methods from a parent compound, which parent compound contains both base and acid moieties. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two (generally anhydrous media, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred). The list of salts can be found in Remington's pharmaceutical sciences,18th ed. (Mack Publishing Company, 1990).

The compounds of the present invention may also be prepared as esters, e.g., pharmaceutically acceptable esters. For example, a carboxylic acid functional group in a compound may be converted to its corresponding ester, such as a methyl, ethyl, or other ester. In addition, the alcohol groups in the compounds can be converted to their corresponding esters, such as acetates, propionates or other esters.

The compounds of the present invention may also be prepared as prodrugs, for example, pharmaceutically acceptable prodrugs. The terms "prodrug" and "prodrug" are used interchangeably in the present invention and refer to any compound that releases an active parent drug in vivo. Since prodrugs are known to enhance various desirable properties of drugs (e.g., solubility, bioavailability, manufacturability, etc.), the compounds may be delivered in prodrug form. Thus, the compounds described herein are intended to encompass prodrugs of the presently claimed compounds, methods of delivering the same, and compositions comprising the same. "prodrug" is intended to include any covalently bonded carrier that releases the active parent drug in vivo when the prodrug is administered to a subject. Prodrugs can be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, from the parent compound. Prodrugs include compounds wherein a hydroxy, amino, mercapto, carboxyl or carbonyl group is bonded to any group that can be cleaved in vivo to form a free hydroxy, free amino, free sulfhydryl, free carboxyl or free carbonyl group, respectively. Prodrugs can also include precursors (forenerers) of the compounds described herein that undergo chemical transformation by metabolic processes before becoming more active or more active pharmaceutical agents or active compounds described herein.

Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetate, formate, phosphate, sulfate, and benzoate derivatives) and carbamates (e.g., N-dimethylaminocarbonyl) of hydroxy functional groups; ester groups of carboxyl functional groups (e.g., ethyl esters, morpholino ethanol esters); n-acyl derivatives of amino functions (e.g. N-acetyl) N-Mannich bases (N-Mannich bases), Schiff bases (Schiff bases) and enaminones; oximes, acetals, ketals, enol esters of ketone and aldehyde functional groups in the compounds, and the like, as well as sulfides which oxidize to form sulfoxides or sulfones.

The term "protecting group" means a group that masks, reduces or blocks a reactive group in a molecule when attached to the reactive groupA set of atoms that stops its reactivity. Examples of Protective Groups are available in Green and Wuts, Protective Groups in organic Chemistry, (Wiley,2.sup. nd ed.1991); harrison and Harrison et al, Compendium of Synthetic Organic Methods, Vols.1-8(John Wiley and Sons,1971-^rded.2003).

The term "amine protecting group" refers to a functional group that converts an amine, amide, or other nitrogen-containing moiety into a different chemical group that is substantially inert to the particular chemical reaction conditions. The amine protecting group is preferably easily and selectively removable in good yield without affecting the other functional groups of the molecule. Examples of amine protecting groups include, but are not limited to, formyl, acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, t-butoxycarbonyl (Boc), p-methoxybenzyl, methoxymethyl, tosyl, trifluoroacetyl, Trimethylsilyl (TMS), fluorenyl-methoxycarbonyl, 2-trimethylsilyl-ethoxycarbonyl, 1-methyl-1- (4-diphenyl) ethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl (CBZ), 2-trimethylsilyl-ethanesulfinyl (SES), triphenyl and substituted triphenyl radicals, 9-Fluorenylmethoxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC), and the like. Those skilled in the art can identify other suitable amine protecting groups.

Representative hydroxy protecting groups include those in which the hydroxy group is acylated or alkylated, such as benzyl and triphenyl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.

In addition, salts of the compounds of the present invention may exist in hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include the monohydrate, dihydrate, and the like. Non-limiting examples of solvates include ethanol solvates, acetone solvates, and the like.

The term "solvate" refers to a solvent addition form comprising a stoichiometric amountOr non-stoichiometric solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming solvates. If the solvent is water, the solvent compound formed is a hydrate, and if the solvent is an alcohol, the solvent formed is an alcoholate. Hydrates are formed by combining one or more molecules of water with a substance in which the water retains its H₂Molecular state of O, this combination being capable of forming one or more hydrates.

The compounds, salts and prodrugs of the present invention may exist in a variety of tautomeric forms, including enol and imine forms, keto and enamine forms, and geometric isomers and mixtures thereof. Tautomers exist in solution as mixtures of tautomeric sets (tautomeric sets). In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present application includes all tautomers of the compounds of the invention. A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This reaction results in formal migration of the hydrogen atoms with concomitant switching of adjacent conjugated double bonds. In a solution where tautomerism may exist, a state of chemical equilibrium of the tautomer will be reached. The exact ratio of tautomers depends on a variety of factors including temperature, solvent and pH. The concept of tautomers that are interconverted by tautomerism is referred to as tautomerism.

Of the many types of interconversion that may exist, two are common. In keto-enol tautomerism, simultaneous displacement of electrons and hydrogen atoms occurs.

Tautomerism can be catalyzed by the following process: alkali: 1. deprotonation; 2. forming delocalized anions (e.g., enolates); 3. protonation at different positions of the anion; acid: 1. protonation; 2. forming delocalized cations; 3. deprotonation occurs at various positions adjacent to the cation.

the term "analog" refers to a chemical compound that is structurally similar to another substance, but differs somewhat in composition (either because one atom is replaced by an atom of a different element or a particular functional group is present, or one functional group is replaced by another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance, but the analog differs from the reference compound in structure or origin.

A "patient," "subject," or "host" to be treated by the subject methods may refer to a human or non-human animal, such as a mammal, fish, bird, reptile, or amphibian. Thus, the subject of the presently disclosed methods can be a human, a non-human primate, a horse, a pig, a rabbit, a dog, a sheep, a goat, a cow, a cat, a guinea pig, or a rodent. The term does not indicate a particular age or gender. Thus, both adult and newborn subjects, as well as fetuses (whether male or female) will be encompassed. In one aspect, the subject is a mammal. A patient refers to a subject suffering from a disease or disorder.

The terms "prophylactic" or "therapeutic" treatment are art-recognized and include administration of one or more of the subject compositions to a host. If administered prior to clinical manifestation of the undesired disorder (e.g., disease or other undesired state of the host animal), the treatment is prophylactic, i.e., it protects the host from developing the undesired disorder, while if administered after manifestation of the undesired disorder, the treatment is therapeutic (i.e., it is intended to eliminate, slow down, or stabilize the existing undesired disorder or side effects thereof).

The terms "therapeutic agent," "drug," "medicament," and "biologically active substance" are art-recognized and include molecules and other agents of biologically, physiologically, or pharmacologically active substances, wherein the active substance acts locally or systemically in a patient or subject to treat a disease or disorder. The term includes, but is not limited to, pharmaceutically acceptable salts and prodrugs. Such agents may be acidic, basic or salt; they may be neutral molecules, polar molecules or molecular complexes bonded to hydrogen; they may be prodrugs of ethers, esters, amides, etc., which are biologically active when administered to a patient or subject.

The phrase "therapeutically effective amount" or "pharmaceutically effective amount" is a term recognized in the art. In certain embodiments, the term refers to the amount of a therapeutic agent that produces a certain desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to an amount necessary or sufficient to eliminate, reduce, or maintain the goal of a particular treatment regimen. The effective amount may vary depending on factors such as the disease or condition to be treated, the particular targeting construct to be administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine an effective amount of a particular compound without undue experimentation. In certain embodiments, a therapeutically effective amount of a therapeutic agent for in vivo use may depend on a variety of factors, including the rate of release of the agent from the polymer matrix, which will depend in part on the chemical and physical characteristics of the polymer; the nature of the agent; modes and methods of administration; and any other substance than the agent incorporated into the polymer matrix.

The term "ED 50" is art recognized. In certain embodiments, ED50 refers to the dose of a drug product that produces 50% of its maximal response or effect, or alternatively, the dose of a drug product that produces a predetermined response in 50% of test subjects or preparations. The term "LD 50" is art recognized. In certain embodiments, LD50 refers to the dose of a pharmaceutical product that is lethal to 50% of test subjects. The term "therapeutic index" is a art-recognized term that refers to the therapeutic index of a pharmaceutical product, and is defined as LD50/ED 50.

The term "IC₅₀"or" semi-inhibitory concentration "refers to the concentration of a substance (e.g., a compound or drug) required to inhibit 50% of a biological process or component of a process (including proteins, subunits, organelles, nucleoproteins, etc.).

For any chemical compound, this application is intended to include all isotopes of atoms present in the compounds of the invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example, but not by way of limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

When the bond formed with a substituent shows a bond spanning 2 atoms in the connecting ring, then such substituent may be bonded to any atom in the ring. When a listed substituent is not indicated as having such an atom through which such substituent is bonded to the remainder of the compound of a given formula, then such substituent may be bonded through any atom in such substituent. Combinations of substituents and/or variants are possible, as long as such combinations result in stable compounds.

When an atom or chemical moiety is followed by a subscript number range (e.g. C)_1-6) It is intended to cover each number within the range and all intermediate ranges. E.g. "C_1-6Alkyl "is meant to include alkyl groups having 1,2, 3,4, 5,6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6 carbons.

The term "alkyl" is intended to include branched (e.g., isopropyl, t-butyl, isobutyl), straight-chain (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), and cycloalkyl (e.g., alicyclic) groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. Such aliphatic hydrocarbon groups have a specific number of carbon atoms. E.g. C_1-6Alkyl is intended to include C₁、C₂、C₃、C₄、C₅And C₆An alkyl group. As used herein, "lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms in the backbone of the carbon chain. "alkyl" further includes alkyl groups having oxygen, nitrogen, sulfur or phosphorus atoms replacing one or more of the carbon atoms of the hydrocarbon backbone. In certain embodiments, the linear or branched alkyl group has 6 or fewer carbon atoms in its backbone (e.g., linear is C)₁-C₆The branched chain is C₃-C₆) For example 4 or less. Similarly, certain cycloalkyl groups have 3 to 8 carbons in their ring structureAn atom, for example, having 5 or 6 carbons in the ring structure.

the term "substituted alkyl" refers to an alkyl moiety in which a substituent replaces a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid, sulfuric acid, alkylsulfinyl, sulfonic acid, sulfonamide, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyl groups may be further substituted, for example, with substituents described above. An "alkylaryl" or "arylalkyl" moiety is an aryl-substituted alkyl group (e.g., phenylmethyl (benzyl)). The terms "alkyl" and "lower alkyl" if not otherwise indicated include linear, branched, cyclic, unsubstituted, substituted and/or heteroatom-containing alkyl or lower alkyl, respectively.

The term "alkenyl" refers to a linear, branched, or cyclic hydrocarbyl group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, tetracosenyl, cyclopentenyl, cyclohexene, cyclooctenyl, and the like. Typically, although not necessary, alkenyl groups can contain 2 to about 18 carbon atoms, more specifically 2 to 12 carbon atoms. The term "lower alkenyl" refers to an alkenyl group of 2 to 6 carbon atoms, and the specific term "cycloalkenyl" refers to a cyclic alkenyl group, preferably having 5 to 8 carbon atoms. The term "substituted alkenyl" refers to alkenyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkenyl" and "heteroalkenyl" refer to alkenyl or heterocycloalkenyl (e.g., heterocyclohexene) in which at least one carbon atom is replaced with a heteroatom. The terms "alkenyl" and "lower alkenyl", if not otherwise indicated, include linear, branched, cyclic, unsubstituted, substituted and/or heteroatom-containing alkenyl and lower alkenyl groups, respectively.

The term "alkynyl" refers to a linear or branched hydrocarbyl group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, and the like. Typically, although not necessary, alkynyl groups can contain 2 to about 18 carbon atoms, and more particularly can contain 2 to 12 carbon atoms. The term "lower alkynyl" refers to alkynyl groups of 2 to 6 carbon atoms. The term "substituted alkynyl" refers to alkynyl groups substituted with one or more substituent groups, and the terms "heteroatom-containing alkynyl" and "heteroalkynyl" refer to alkynyl groups in which at least one carbon atom is replaced with a heteroatom. The terms "alkynyl" and "lower alkynyl" include linear, branched, unsubstituted, substituted and/or heteroatom-containing alkynyl or lower alkynyl groups, respectively, if not otherwise indicated.

The terms "alkyl", "alkenyl" and "alkynyl" are intended to include moieties which are diradicals, i.e., having 2 points of attachment. A non-limiting example of the alkyl portion of such diradicals is-CH₂CH₂-, i.e. C covalently bonded to the remainder of the molecule through each terminal carbon atom₂an alkyl group.

The term "alkoxy" refers to an alkyl group bonded through a single terminal ether linkage; that is, an "alkoxy" group may be represented as-O-alkyl, where alkyl is as defined above. "lower alkoxy" group refers to an alkoxy group containing 1 to 6 carbon atoms and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy and the like. Identified herein as "C₁-C₆Preferred substituents for alkoxy "or" lower alkoxy "contain 1 to 3 carbon atoms, and particularly preferred such substituents contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).

The term "aryl" refers to an aromatic substituent comprising a single aromatic ring or multiple aromatic rings fused together (either by direct or indirect linkage) (such that different aromatic rings are bonded to a common group, e.g., a methylene or ethylene moiety). The aryl group may contain 5 to 20 carbon atoms, and a particularly preferred aryl group may contain 5 to 14 carbon atoms. Examples of aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, the term "aryl" includes polycyclic aryl groups, such as tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles," heteroaryls, "or" heteroaromatics. The aromatic rings may be substituted at one or more ring positions with such substituents as described above, for example, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphoric acid, phosphonic acid, phosphinic acid, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid, sulfuric acid, alkylsulfinyl, sulfonic acid, or a salt thereof, Sulfonamide, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. The aryl groups may also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic, thereby forming polycyclic ring systems (e.g., tetrahydronaphthalene, methylenedioxyphenyl). The term "aryl" includes unsubstituted, substituted and/or heteroatom-containing aromatic substituents, if not otherwise indicated.

The term "alkaryl" refers to an aryl group having an alkyl substituent, and the term "aralkyl" refers to an alkyl group having an aryl substituent, wherein "aryl" and "alkyl" are as defined above. Exemplary aralkyl groups contain 6 to 24 carbon atoms, and particularly preferred aralkyl groups contain 6 to 16 carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, and the like. Alkylaryl groups include, for example, p-methylphenyl, 2, 4-dimethylphenyl, p-cyclohexylphenyl, 2, 7-dimethylnaphthyl, 7-cyclooctylphenyl, 3-ethyl-cyclopenta-1, 4-diene, and the like.

The term "heterocyclyl" or "heterocyclic group" includes closed ring structures, such as 3-to 10-, or 4-to 7-membered rings, which contain one or more heteroatoms. "heteroatom" includes atoms of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur, and phosphorus.

heterocyclyl groups may be saturated or unsaturated and include pyrrolidine, oxolane, tetrahydrothiophene, piperidine, piperazine, morpholine, lactones, lactams (e.g., azetidinone and pyrrolidone), sultams, and sultones. Heterocyclic groups (e.g., pyrrole and furan) may have aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other examples of heterocyclic groups include pyridine and purine. The heterocyclic ring may be substituted at one or more positions with substituents such as those described above, for example halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid group, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxy, phosphoric acid group, phosphonic acid group, phosphinic acid group, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea)Group), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid group, sulfuric acid group, sulfonic acid, sulfonamide, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic group, or an aromatic or heteroaromatic moiety. The heterocyclic group may also be substituted at one or more substituent atoms by, for example, lower alkyl, lower alkenyl, lower alkoxy, lower alkylthio, lower alkylamino, lower alkylcarboxyl, nitro, hydroxy, -CF₃or-CN, etc.

The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. "counterions" are used to represent species of small negative charge, such as fluoride, chloride, bromide, iodide, hydroxide, acetate, and sulfate. The term sulfoxide refers to sulfur attached to 2 different carbon atoms and 1 oxygen, and an S-O bond can be represented graphically as a double bond (S ═ O), a single bond with no charge (S-O), or a single bond with a charge [ S (+) -O (-) ].

As referred to in some of the above definitions, the term "substituted" as used in "substituted alkyl", "substituted aryl", and the like, means that at least one hydrogen atom bonded to a carbon (or other) atom is replaced with one or more non-hydrogen substituents in the alkyl, aryl, or other moiety. Examples of such substituents include, but are not limited to, functional groups such as halogen, hydroxy, silyl, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀Aryloxy, acyl (including C)₂-C₂₄Alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkyl carbonic acid (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO-), carbamoyl (- (CO) -NH₂) Mono- (C)₁-C₂₄Alkyl) -substituted carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl))Bis- (C)₁-C₄Alkyl) -substituted carbamoyl (- (CO) -N (C)₁-C₂₄Alkyl radical)₂) Mono-substituted arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-ON)⁺C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂) Mono-and bis- (C)₁-C₂₄Alkyl) -substituted amino, mono-and bis- (C)₅-C₂₀Aryl) -substituted amino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), imino (-CR- ═ NH-where R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀Aryl radical, C₆-C₂₄alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄Alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂Alkyl), C₅-C₂₀Arylsulfonyl (-SO)₂Aryl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) And phosphino (-PH)₂) (ii) a And a hydrocarbyl moiety C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄Alkynyl, C₅-C₂₀Aryl radical, C₆-C₂₄Alkylaryl and C₆-C₂₄An aralkyl group.

Furthermore, the above-mentioned functional groups are further substituted, if permitted by a particular group, with one or more other functional groups or one or more hydrocarbyl moieties, such as those specifically enumerated above. Similarly, the hydrocarbyl moieties mentioned above may be further substituted with one or more functional groups or other hydrocarbyl moieties, such as those specifically enumerated.

When the term "substituted" appears before a list of groups that may be substituted, it means that the term applies to each member of the list. For example, the phrase "substituted alkyl, alkenyl, and aryl" will be interpreted as "substituted alkyl, substituted alkenyl, and substituted aryl". Similarly, when the term "heteroatom-containing" appears before a list of possible heteroatom-containing groups, it is meant that the term applies to each member of the list. For example, the phrase "heteroatom-containing alkyl, alkenyl, and aryl" is interpreted to mean "heteroatom-containing alkyl, substituted alkenyl, and substituted aryl".

"optional" or "optionally" means that the subsequently described condition may or may not occur, such that the description includes instances where the condition occurs and instances where it does not. For example, the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present on a given atom, and thus the description includes structures in which a non-hydrogen substituent is present as well as structures in which a non-hydrogen substituent is not present.

The terms "stable compound" and "stable structure" refer to a compound that is sufficiently robust to survive isolation and, where appropriate, purification from a reaction mixture, and formulation into an effective therapeutic agent.

The term "free compound" is used herein to describe a compound in an unbound state.

Throughout the specification, compositions are described as having, containing, or comprising specific ingredients, it is contemplated that the compositions also consist essentially of, or consist of, the recited ingredients. Similarly, a method or process is described as having, containing, or comprising specific process steps, which process also consists essentially of, or consists of, the recited process steps. Further, it is to be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remain operable. Further, two or more steps or actions may be performed concurrently.

The term "small molecule" is a term recognized in the art. In certain embodiments, the term refers to molecules having a molecular weight of less than about 2000amu, or less than about 1000amu, and even less than about 500 amu.

All percentages and ratios used herein are by weight unless otherwise indicated.

the term "neoplasm (neoplasms)" refers to any abnormal occupancy of a cell or tissue as a result of neoplasia. A neoplasm can be benign, potentially malignant (precancerous) or malignant (cancerous). Adenomas are examples of neoplasms.

the terms "adenoma", "colonic adenoma" and "polyp" are used herein to describe any precancerous neoplasm of the colon.

As used herein, the term "colon" is meant to encompass the right colon (including the cecum), the transverse colon, the left colon, and the rectum.

The terms "colorectal cancer" and "colon cancer" are used interchangeably herein to refer to any cancerous neoplasia of the colon (including the rectum as defined above).

The term "gene expression" or "protein expression" includes any information about the amount of gene transcript or protein present in a sample, as well as information about the rate of gene or protein production, or accumulation, or degradation (e.g., reporter gene data, data from a nuclear runoff test, pulse trace data, etc.). Certain data can be considered to be related to gene and protein expression. For example, the level of a protein in a cell reflects the level of the protein as well as the level of transcription, and such data is included in the phrase "gene or protein expression information". Such information can be given in unitless measure in terms of amount per cell, relative to the amount of a control gene or protein; the term "information" is not limited to any particular means of presentation and refers to any presentation that provides relevant information. The term "expression level" refers to a quantification reflected or derived from gene or protein expression data, whether or not the data relates to gene transcript accumulation or protein synthesis rate, and the like.

The terms "healthy" and "normal" are used interchangeably herein and refer to a subject or a particular cell or tissue that lacks (at least to the limit of detection) a disease condition.

The term "nucleic acid" refers to polynucleotides, such as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA). The term should also be understood to encompass analogs of RNA or DNA made from nucleotide analogs, as well as single-stranded (e.g., sense or antisense) and double-stranded polynucleotides (where the embodiments are applied). In some embodiments, "nucleic acid" refers to inhibitory nucleic acids. Some classes of inhibitory nucleic acid compounds include antisense nucleic acids, RNAi constructs, and catalytic nucleic acid constructs. Nucleic acids of this class are well known in the art.

Embodiments described herein relate to compounds and methods for modulating SCD activity (e.g., 15-PGDH activity), modulating tissue prostaglandin levels, and/or treating diseases, disorders, or conditions in which modulation of 15-PGDH activity and/or prostaglandin levels is desired.

"inhibitor," "activator," and "modulator" of 15-PGDH expression or 15-PGDH activity are used to refer to inhibitory, activating, or modulating molecules, e.g., ligands, agonists, antagonists, and homologs and mimetics thereof, identified by in vitro and in vivo testing of 15-PGDH expression or 15-PGDH activity, respectively. The term "modulator" includes inhibitors and activators. An inhibitor is, for example, an agent, e.g., an antagonist, that inhibits or binds to the expression of 15-PGDH, thereby partially or completely blocking the stimulation, decreasing, preventing, delaying activation, inactivating, desensitizing, or down-regulating the activity of 15-PGDH. An activator is, for example, an agonist that induces or activates expression of 15-PGDH or binds thereto, thereby stimulating, stabilizing, increasing, opening, activating, promoting or enhancing the activity of 15-PGDH, rendering 15-PGDH sensitive or up-regulating the activity of 15-PGDH. Modulators include naturally occurring and synthetic ligands, small chemical molecules, and the like.

The 15-PGDH inhibitors described herein can provide pharmacological methods for elevating prostaglandin levels in tissues. Known activities of prostaglandins include promoting hair growth, promoting skin pigmentation, and promoting the appearance of skin tanning or skin tanning. Known activities of prostaglandins also include the reduction of pulmonary hypertension. The 15-PGDH inhibitors described herein may also be used to increase the number of tissue stem cells for a variety of purposes, including increasing resistance to radiation-induced tissue damage, increasing resistance to environmental exposure to radiation, increasing the number of stem cells to increase the fitness of bone marrow or other transplant types (by in vivo exposure to the 15-PGDH inhibitors described herein, thereby increasing the number of stem cells prior to harvesting of the transplanted tissue; or by ex vivo exposure of harvested tissue prior to transplantation into a recipient host, or by treatment of the transplant recipient). The 15-PGDH inhibitors described herein may also be used for a variety of purposes, including promoting liver regeneration, including liver regeneration after liver resection, liver regeneration after toxin infection (toxinic inhibitors), which may be caused, for example, by acetaminophen overdose. Prostaglandin signaling is also known to promote wound healing, protect the stomach from ulcers, and promote healing of gastric and intestinal ulcers. Furthermore, the 15-PGDH inhibitors described herein can promote the activity of human keratinocytes in the "healing" scratch of keratinocyte cultures. Thus, the 15-PGDH inhibitors described herein may also be used to heal ulcers of other tissues, including but not limited to the skin, and including but not limited to diabetic ulcers. In addition, the 15-PGDH inhibitors described herein may be used to treat erectile dysfunction.

The 15-PGDH inhibitors described herein can be identified using a variety of assays, in which putative modulator compounds are applied to 15-PGDH-expressing cells, and then the functional effect on 15-PGDH activity is determined. The extent of action is determined by comparing a sample or test comprising 15-PGDH treated with a potential activator, inhibitor or modulator with a control sample not treated with an inhibitor, activator or modulator. Control samples (not treated with modulator) were assigned a relative 15-PGDH activity value of 100%. Inhibition of 15-PGDH is achieved when the activity value of 15-PGDH is about 80%, optionally 50%, 25%, 10%, 5% or 1% relative to the control.

the reagent to be tested as a modulator of SCD (e.g., 15-PGDH) may be any small chemical molecule or compound. Typically, the test compound is a small chemical molecule, a natural product, or a peptide. The tests are designed to screen large chemical libraries by automated testing steps and providing compounds from any convenient source to the test (which is usually run in parallel, for example in microtiter format on microtiter plates in machine tests). Modulators also include agents designed to increase the level of 15-PGDHmRNA or the level of translation from mRNA.

In some embodiments, the modulator of SCD may be an SCD inhibitor, which may be administered to the tissue or blood of a subject in an amount effective to inhibit short chain dehydrogenase activity. The SCD inhibitor may be a 15-PGDH inhibitor, which may be administered to a tissue or blood of a subject in an amount effective to increase prostaglandin levels in the tissue or blood. The 15-PGDH inhibitor may include a compound having formula (I) or (II):

Wherein X¹Is N or CR⁴；

X²Is S, S ═ O, S (═ O)₂Or C ═ O;

X³Is CR⁸(the compound forms a polycyclic heteroaryl group having 10 ring atoms) or absent (the compound forms a polycyclic heteroaryl group having 9 ring atoms);

X⁴Is N, NH or CR⁷；

X⁵Is N, C ═ O or CR¹⁶(ii) a And if X⁴Is CR⁷Or X³Is absent, X⁵Is N; if X is⁵Is C ═ O, X⁴Is NH; and such asFruit X⁴Is N and X³Is CR⁸，X⁵Is CR¹⁶；

R¹、R²、R³、R⁴、R⁹、R¹⁰And R¹⁶Are the same or different and are independently selected from the group consisting of hydrogen, oxygen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄alkynyl, C₃-C₂₀Aryl, heterocycloalkenyl containing 5-7 ring atoms (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of the ring atoms are independently selected from N, NH, N (C)₁-C₃Alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀Aryloxy, acyl (including C)₂-C₂₄Alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO), carbamoyl (- (CO) -NH₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄Alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀Aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄Alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂Alkyl), C_5-C₂₀Arylsulfonyl (-SO)₂Aryl), sulfonamides (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH)₂)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]Groups comprising amino acids or other moieties predicted to carry a positive or negative charge at physiological pH, and combinations thereof;

R⁷And R⁸Are the same or different and are each independently selected from the group consisting of H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclylAre of the group, and R⁷Or R⁸Is not H; and pharmaceutically acceptable salts thereof.

In some embodiments, R²Or R³Is not H, and R⁹Or R¹⁰Is not H.

In some embodiments, the 15-PGDH inhibitor may comprise a compound having the following formula (Ia):

Wherein X²Is S, S ═ O, S (═ O)₂Or C ═ O;

Each R¹、R²And R³Are the same or different and are independently selected from hydrogen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₀Aryl, heterocycloalkenyl containing 5-7 ring atoms (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of the ring atoms are independently selected from N, NH, N (C)₁-C₃Alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀Aryloxy, acyl (including C)₂-C₂₄Alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate(-COO), carbamoyl (- (CO) -NH)₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄Alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀Aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄Alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂alkyl), C₅-C₂₀Arylsulfonyl (-SO)₂-aryl), aminosulfonyl (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphine (-PH2), polyalkyl ether (- [ (C)H2)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]A group comprising an amino acid or other moiety predicted to carry a positive or negative charge at physiological pH, combinations thereof, and R²Or R³Is not H; and pharmaceutically acceptable salts thereof.

In other embodiments, the 15-PGDH inhibitor may comprise a compound having the following formula (Ib):

Wherein X²Is S, S ═ O, S (═ O)₂Or C ═ O;

R²、R³、R⁵And R⁶Are the same or different and are independently selected from hydrogen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₀Aryl, heterocycloalkenyl containing 5-7 ring atoms (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of the ring atoms are independently selected from N, NH, N (C)₁-C₃Alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀Aryloxy, acyl (including C2-C24 alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxy carbonyloxy (-O- (CO) -O-)Aryl), carboxyl (-COOH), carboxylate (-COO)^-) Carbamoyl (- (CO) -NH)₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄Alkylamino radical, C₅-C₂₀arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀Aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄Alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂Alkyl), C₅-C₂₀arylsulfonyl (-SO)₂-aryl), aminosulfonyl (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH)₂)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]A group comprising an amino acid or other moiety predicted to carry a positive or negative charge at physiological pH, combinations thereof, and R²Or R³Is not H; wherein R is⁵And R⁶May be linked to form a ring or a polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; and pharmaceutically acceptable salts thereof.

In other embodiments, the 15-PGDH inhibitor may comprise a compound having the following formula (Ic):

Wherein R is²、R³And R¹⁴Are the same or different and are independently selected from hydrogen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₀Aryl, heterocycloalkenyl containing 5-7 ring atoms (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of the ring atoms are independently selected from N, NH, N (C)₁-C₃alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀Aryloxy, acyl (including C)₂-C₂₄Alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (-CO)(CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO), carbamoyl (- (CO) -NH₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄Alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀Aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O)、C₁-C₂₄Alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂Alkyl), C₅-C₂₀Arylsulfonyl (-SO)₂-aryl), aminosulfonyl (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH)₂)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]A group comprising an amino acid or other moiety predicted to carry a positive or negative charge at physiological pH, combinations thereof, and R²Or R³Is not H, n¹Is 0 to 4, and each R¹⁴Are the same or different; and pharmaceutically acceptable salts thereof.

In other embodiments, the 15-PGDH inhibitor may comprise a compound having the following formula (Id):

Wherein X²Is S, S ═ O, S (═ O)₂Or C ═ O;

X⁶Is Cl, Br or F, and y + z ═ 3;

R¹And R³Are the same or different and are independently selected from hydrogen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₀Aryl, heterocycloalkenyl containing 5-7 ring atoms (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of the ring atoms are independently selected from N, NH, N (C)₁-C₃Alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀aryloxy, acylRadical (including C)₂-C₂₄Alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO), carbamoyl (- (CO) -NH₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄Alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂alkyl), C₅-C₂₀arylsulfonyl (-SO)₂-aryl), aminosulfonyl (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH)₂)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]A group comprising an amino acid or other moiety predicted to carry a positive or negative charge at physiological pH, combinations thereof, and R²Or R³Is not H; and pharmaceutically acceptable salts thereof.

in other embodiments, the 15-PGDH inhibitor may comprise a compound having the following formula (Ie):

Wherein X²Is S, S ═ O, S (═ O)₂Or C ═ O;

R¹and R²Are the same or different and are independently selected from hydrogen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₀aryl, heterocycloalkenyl containing 5-7 ring atoms, (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of the ring atoms are independently selected from N, NH, N (C)₁-C₃Alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C24 aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C24 alkoxy, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀Aryloxy, acyl (including C)₂-C₂₄Alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO), carbamoyl (- (CO) -NH₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄Alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀Aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄Alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀ArylsulfinylRadical (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂Alkyl), C₅-C₂₀Arylsulfonyl (-SO)₂-aryl), aminosulfonyl (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH)₂)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂wherein R is H, methyl or other alkyl]A group comprising an amino acid or other moiety predicted to carry a positive or negative charge at physiological pH, combinations thereof, and R²Or R³Is not H; and pharmaceutically acceptable salts thereof.

Examples of 15-PGDH inhibitors having formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) include the following compounds:

And pharmaceutically acceptable salts thereof.

In other embodiments, the 15-PGDH inhibitor may comprise a compound having the following formula (IIa):

Wherein R is⁷And R⁸Are the same or different and are each independently selected from the group consisting of H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkylAnd substituted or unsubstituted heterocyclic group, and R⁷Or R⁸Is not H;

R⁹And R¹⁰Are the same or different and are independently selected from hydrogen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₀Aryl, heterocycloalkenyl containing 5-7 ring atoms (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of the ring atoms are independently selected from N, NH, N (C)₁-C₃alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀aryloxy, acyl (including C)₂-C₂₄Alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO), carbamoyl (- (CO) -NH₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄alkyl radical, C₅-C₂₀Aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄Alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂Alkyl), C₅-C₂₀Arylsulfonyl (-SO)₂-aryl), aminosulfonyl (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH2)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]A group comprising an amino acid or other moiety predicted to carry a positive or negative charge at physiological pH, combinations thereof, and optionally R⁹Or R¹⁰Is not H;

and pharmaceutically acceptable salts thereof.

In other embodiments, the 15-PGDH inhibitor may comprise a compound having the following formula (IIb):

Wherein X⁷Is S, S ═ O, S (═ O)₂Or C ═ O;

R¹¹Selected from hydrogen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₀Aryl, heterocycloalkenyl containing 5 to 7 ring atoms (wherein 1 to 3 of the ring atoms are independently selected from N, NH, N (C1-C)₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of the ring atoms are independently selected from N, NH, N (C)₁-C₃Alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀Aryloxy, acyl (including C)₂-C₂₄Alkylcarbonyl (-CO-alkyl) and C₆-C₂₀arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO), carbamoyl (- (CO) -NH₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄Alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄alkyl radical, C₅-C₂₀Aryl radical, C₆-C₂₄alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄Alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂Alkyl), C₅-C₂₀Arylsulfonyl (-SO)₂-aryl), aminosulfonyl (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH)₂)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]containing amino acids or other moieties predicted to carry a positive or negative charge at physiological pHA group consisting of combinations thereof;

And pharmaceutically acceptable salts thereof.

In some embodiments, the 15-PGDH inhibitor may comprise a compound having the following formula (IIc):

Wherein X⁷Is S, S ═ O, S (═ O)₂Or C ═ O;

R¹²And R¹³are the same or different and are independently selected from hydrogen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₀Aryl, heterocycloalkenyl containing 5-7 ring atoms (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of the ring atoms are independently selected from N, NH, N (C)₁-C₃Alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀Aryloxy, acyl (including C)₂-C₂₄Alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO), carbamoyl (- (CO) -NH₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄Alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀Aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄Alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂Alkyl), C₅-C₂₀Arylsulfonyl (-SO)₂-aryl), aminosulfonyl (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group(-P(O)(O^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH)₂)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]Groups comprising amino acids or other moieties predicted to carry a positive or negative charge at physiological pH, and combinations thereof; wherein R is¹²And R¹³May be linked to form a ring or a polycyclic ring, wherein the ring is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;

And pharmaceutically acceptable salts thereof.

In other embodiments, the 15-PGDH inhibitor may comprise a compound having the following formula (IId):

Wherein X⁷Is S, S ═ O, S (═ O)₂Or C ═ O;

R¹⁵Selected from hydrogen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄alkynyl, C₃-C₂₀Aryl, heterocycloalkenyl containing 5-7 ring atoms, (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of the ring atoms are independently selected from N, NH, N (C)₁-C₃Alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C₂₄alkoxy radical, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀Aryloxy, acyl (including C)₂-C₂₄Alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C2₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO)^-) Carbamoyl (- (CO) -NH)₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄Alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂Alkyl), C₅-C₂₀Arylsulfonyl (-SO)₂-aryl), aminosulfonyl (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH)₂)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]Groups comprising amino acids or other moieties predicted to carry a positive or negative charge at physiological pH, combinations thereof, n²Is 0 to 4, and each R¹⁵Are the same or different;

And pharmaceutically acceptable salts thereof.

in other embodiments, the 15-PGDH inhibitor may comprise a compound having the following formula (IIe):

R⁸Is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;

R¹⁵Is selected from hydrogen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₀Aryl, heterocycloalkenyl containing 5-7 ring atoms, (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl containing 5 to 14 ring atoms orHeterocyclyl (wherein 1-6 of said ring atoms are independently selected from N, NH, N (C)₁-C₃alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C5-C₂₀Aryloxy, acyl (including C)₂-C₂₄Alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO)^-) Carbamoyl (- (CO) -NH)₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄Alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀Aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc) Nitro (-NO)₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄Alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C₁-C₂₄Alkylsulfonyl (-SO)₂Alkyl), C₅-C₂₀Arylsulfonyl (-SO)₂-aryl), aminosulfonyl (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH)₂)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]Groups comprising amino acids or other moieties predicted to carry a positive or negative charge at physiological pH, combinations thereof, n²Is 0 to 4, and each R¹⁵are the same or different;

And pharmaceutically acceptable salts thereof.

In other embodiments, the 15-PGDH inhibitor may comprise a compound having the following formula (IIf):

R⁸Is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;

R¹⁵And R¹⁶Are the same or different and are independently selected from the group consisting of hydrogen, oxygen, substituted or unsubstituted C₁-C₂₄Alkyl radical, C₂-C₂₄Alkenyl radical, C₂-C₂₄Alkynyl, C₃-C₂₀Aryl radicals containing 5 to 7 ring members(iii) heterocycloalkenyl of (wherein 1-3 of the ring atoms are independently selected from N, NH, N (C)₁-C₆Alkyl), NC (O) (C)₁-C₆Alkyl), O and S), heteroaryl or heterocyclyl containing 5-14 ring atoms (wherein 1-6 of said ring atoms are independently selected from N, NH, N (C)₁-C₃Alkyl), O and S), C₆-C₂₄Alkylaryl group, C₆-C₂₄aralkyl, halogen, silyl, hydroxy, mercapto, C₁-C₂₄Alkoxy radical, C₂-C₂₄Alkenyloxy radical, C₂-C₂₄Alkynyloxy, C₅-C₂₀Aryloxy, acyl (including C)₂-C₂₄Alkylcarbonyl (-CO-alkyl) and C₆-C₂₀Arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄Alkoxycarbonyl (- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyl (- (CO) -O-aryl), C₂-C₂₄Alkoxycarbonyloxy (-O- (CO) -O-alkyl), C₆-C₂₀Aryloxycarbonyloxy (-O- (CO) -O-aryl), carboxyl (-COOH), carboxylate (-COO)^-) Carbamoyl (- (CO) -NH)₂)、C₁-C₂₄Alkyl-carbamoyl (- (CO) -NH (C)₁-C₂₄Alkyl)), arylcarbamoyl (- (CO) -NH-aryl), thiocarbamoyl (- (CS) -NH₂) Ureido (-NH- (CO) -NH)₂) Cyano (-CN), isocyano (-N)⁺C^-) Cyanato (-O-CN), isocyanato (-O-N)⁺＝C^-) Isothiocyanato (-S-CN), azido (-N ═ N)⁺＝N^-) Formyl (- (CO) -H), thioaldehyde (- (CS) -H), amino (-NH)₂)、C₁-C₂₄Alkylamino radical, C₅-C₂₀Arylamino, C₂-C₂₄Alkylamido (-NH- (CO) -alkyl), C₆-C₂₀Arylamido (-NH- (CO) -aryl), sulfonamido (-SO)₂N(R)₂Wherein R is independently H, alkyl, aryl or heteroaryl), imino (-CR ═ NH wherein R is hydrogen, C₁-C₂₄Alkyl radical, C₅-C₂₀Aryl radical, C₆-C₂₄Alkylaryl group, C₆-C₂₄Aralkyl, etc.), alkylimino (-CR ═ N (alkyl), where R ═ hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR ═ N (aryl), where R ═ hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO), and the like₂) Nitroso group (-NO), sulfonic group (-SO)₂-OH), sulfonate (-SO)₂-O^-)、C₁-C₂₄Alkylthio (-S-alkyl; also known as "alkylthio"), arylthio (-S-aryl; also known as "arylthio"), C₁-C₂₄Alkylsulfinyl (- (SO) -alkyl), C₅-C₂₀Arylsulfinyl (- (SO) -aryl), C1-C₂₄Alkylsulfonyl (-SO)₂Alkyl), C₅-C₂₀Arylsulfonyl (-SO)₂-aryl), aminosulfonyl (-SO)₂-NH₂、-SO₂NY₂(wherein Y is independently H, aryl or alkyl), phosphono (-P (O) (OH)₂) Phosphonic acid group (-P (O) (O))^-)₂) Phosphinic acid group (-P (O) (O))^-) Phosphorus oxide (-PO), phosphorus oxide₂) Phosphino (-PH)₂) Poly alkyl ether (- [ (CH)₂)_nO]_m) Phosphate, phosphate [ -OP (O) (OR)₂Wherein R is H, methyl or other alkyl]Groups comprising amino acids or other moieties predicted to carry a positive or negative charge at physiological pH, combinations thereof, n²Is 0 to 4, and each R¹⁵Are the same or different;

And pharmaceutically acceptable salts thereof.

Examples of the 15-PGDH inhibitor having (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) may include the following compounds:

And pharmaceutically acceptable salts thereof.

In certain embodiments, a 15-PGDH inhibitor having formula (I) and (II) may be selected, which may: ia) stimulating a Vaco503 reporter cell line (reportercell line) expressing the 15-PGDH luciferase fusion construct at a concentration of 2.5 μ M such that the luciferase production level is above 70 (using a scale on which values of 100 indicate a two-fold increase in reported production (reporter output) over baseline); iia) stimulating the V9M reporter cell line expressing the 15-PGDH luciferase fusion construct at a concentration of 2.5 μ M, such that the luciferase production levels are above 75; iiia) stimulating the LS174T reporter cell line expressing the 15-PGDH luciferase fusion construct at a concentration of 7.5 μ M, such that the luciferase production levels were above 70; and iva) failed to activate the negative control V9M cell line expressing the TK-renilla luciferase reporter to a level above 20 at a concentration of 7.5 μ M; and va) IC at less than 1 μ M₅₀Inhibiting the enzymatic activity of the recombinant 15-PGDH protein.

In other embodiments, the 15-PGDH inhibitor may: ib) stimulating a Vaco503 reporter cell line expressing the 15-PGDH luciferase fusion construct at a concentration of 2.5 μ M, thereby increasing luciferase production; iib) stimulating a V9M reporter cell line expressing the 15-PGDH luciferase fusion construct at a concentration of 2.5 μ M, thereby increasing luciferase production; iiib) at a concentration of 7.5 μ M, stimulating the LS174T reporter cell line expressing the 15-PGDH luciferase fusion construct, thereby increasing luciferase production; ivb) failed to activate the negative control V9M cell line expressing the TK-renilla luciferase reporter at 7.5 μ M concentration to a luciferase level above 20% background; and vb) IC at less than 1 μ M₅₀Inhibiting the enzymatic activity of the recombinant 15-PGDH protein.

In other embodiments, the 15-PGDH inhibitor may be present at a recombinant 15-PGDH concentration of about 5nM to about 5nMAt an IC of less than 1 μ M at about 10nM₅₀or preferably at an IC of less than 250nM₅₀Or more preferably at an IC of less than 50nM₅₀Or more preferably at an IC of less than 10nM₅₀Or more preferably at an IC of less than 5nM₅₀Inhibiting the enzymatic activity of recombinant 15-PGDH.

In other embodiments, the 15-PGDH inhibitor may increase the cellular level of PGE-2 following stimulation of A459 cells with a suitable agent (e.g., IL1- β).

The 15-PGDH inhibitors described herein may be used for the prevention or treatment of a disease associated with 15-PGDH and/or decreased levels of prostaglandins, and/or a disease requiring increased levels of prostaglandins in a subject. For example, as noted above, prostaglandins are known to play an important role in hair growth. Specifically, a plurality of types (A) have been shown₂,F_2a,E₂) The internal storage of prostaglandins in hair follicles or their adjacent skin environment is essential in maintaining and increasing hair density (Colombe L et al,2007, exp. dermatol,16(9), 762-9). 15-PGDH, which is involved in degradation of prostaglandins, has been reported to be present in dermal papillae of hair follicles (PGF in particular)_2aAnd PGE₂) Inactivation, resulting in scalp damage and hair loss (Michelet J F et al, 2008, exp. dermatol,17(10), 821-8). Therefore, the compound described herein, which has a suppressing or inhibiting activity against 15-PGDH degrading prostaglandins, can improve scalp damage, prevent hair loss and promote hair growth, and can be used in a pharmaceutical composition for preventing hair loss and promoting hair growth.

In other embodiments, the 15-PGDH inhibitors described herein may be used in pharmaceutical compositions for promoting and/or inducing and/or stimulating pigmentation of the skin and/or skin appendages, and/or as agents for preventing and/or limiting discoloration and/or whitening of the skin and/or skin appendages, in particular as agents for preventing and/or limiting canities.

In some embodiments, the 15-PGDH inhibitor may be administered to the skin of a subject, for example in a topical application, to promote and/or stimulate pigmentation and/or hair growth of the skin, inhibit hair loss, and/or treat skin damage or inflammation, for example skin damage caused by physical or chemical irritants and/or UV exposure.

In other embodiments, the 15-PGDH inhibitors described herein may be used for the prevention or treatment of cardiovascular diseases and/or vascular insufficiency diseases, such as raynaud's disease, buerger's disease, diabetic neuropathy and pulmonary hypertension. Prostaglandins (including prostaglandin homologues produced in the body) are known to maintain the proper function of the vessel wall, in particular to assist vasodilation for blood flow, prevent platelet coagulation and regulate proliferation of smooth muscle around the vessel wall (yan. chengt. al.,2006, j.clin., Invest). Inhibition of prostaglandin production and loss of its activity leads to degeneration of the vascular wall endothelium, platelet aggregation, and dysfunction of cellular mechanisms in smooth muscle. Among these, prostaglandin production in blood vessels has been shown to be reduced in hypertensive patients, including pulmonary hypertension.

In other embodiments, the 15-PGDH inhibitors described herein can be used in pharmaceutical compositions for the prevention or treatment of oral, intestinal and/or gastrointestinal tract injuries or diseases or inflammatory bowel disease, such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, and gastric ulcers. Gastritis or gastric ulcer, which are representative of gastrointestinal diseases, is defined as a condition in which the gastrointestinal mucosa is digested by gastric acid to form an ulcer. In the stomach wall, which is usually composed of mucosa, submucosa, muscle layer and chorion, gastric ulcers even damage the submucosa and muscle layer, while gastritis only damages the mucosa. Although the incidence of gastritis and gastric ulcers is relatively high, the cause has not been clarified. Until now, they have been known to be caused by an imbalance between invasive and defensive factors, in other words, an increase in invasive factors (e.g. an increase in gastric acid or pepsin secretion), or a decrease in defensive factors (e.g. structural or morphological defects of the gastric mucosa), a decrease in the secretion of mucosal and bicarbonate ions, a decrease in prostaglandin production, etc.

Currently available therapeutic agents for gastritis and gastric ulcer include various drugs for strengthening defensive factors, such as antacids (which do not affect gastric acid secretion but can neutralize already produced gastric acid), inhibitors of gastric acid secretion, promoters of prostaglandin secretion and coating agents (coating agents) of gastric wall. In particular, prostaglandins are known to be important in maintaining the mechanisms for protecting and defending the gastric mucosa (Wallace J l.,2008, Physiol rev.,88(4),1547-65, s.j. konturn et al, 2005, Journal of Physiology and Pharmacology,56 (5)). In view of this, since the 15-PGDH inhibitors according to the present invention show inhibitory or inhibitory activity against 15-PGDH, which degrades prostaglandins protecting gastric mucosa, they can be effectively used for preventing or treating gastrointestinal diseases, particularly gastritis and gastric ulcer.

In addition, it is also contemplated that 15-PGDH inhibitors may protect against other forms of intestinal injury, including toxicity due to radiation, toxicity due to chemotherapy, and chemotherapy-induced mucositis.

In the kidney, prostaglandins regulate blood flow in the kidney and can act to regulate urine formation through renal vascular and vascular actions. In clinical studies, PGE₁Have been used to improve creatinine clearance in patients with chronic kidney disease, thereby preventing graft rejection and cyclosporin toxicity in patients with renal transplantation, thereby reducing urinary albumin excretion and N-acetyl- β -D-glucosaminidase levels in patients with diabetic nephropathy (see Porter, Am.,1989, J. Cardiol.,64: 22E-26E). In addition, U.S. patent No. 5,807,895 discloses the intravenous administration of prostaglandins (e.g., PGEs)₁、PGE₂And PGI₂) To prevent renal insufficiency. In addition, prostaglandins have been reported to act as vasodilators in the kidney, thus inhibiting prostaglandin production in the kidney leads to renal insufficiency (hao.c. M,2008, Annu Rev Physiol,70,357, about.77).

Thus, the 15-PGDH inhibitors described herein, which have suppressive or inhibitory activity against 15-PGDH that degrades prostaglandins, are effective in preventing or treating renal disease associated with renal insufficiency.

As used herein, the term "renal insufficiency" includes the following manifestations: less than normal creatinine clearance, less than normal free water clearance, greater than normal hematuria, nitrogen, potassium and/or creatinine levels, increased renal enzyme activity (e.g., gamma-glutamyl synthetase, alanine phospholipase, N-acetyl-beta-D-glucosaminidase or beta-w-microglobulin), and increased levels of proteinuria above normal.

Prostaglandins (including PGE)₁、PGE₂And PGF_2a) It has also been shown to stimulate bone resorption and bone formation, thereby increasing bone volume and strength (h.kawaguchi et al, Clinical ortho.rel.res., 313,1995; j.keller et al, eur.jr.exp.musculoskeltel res, 1,1992,8692). Given that 15-PGDH will inhibit prostaglandin activity as described above, inhibition of 15-PGDH activity may promote 15-PGDH-inhibited bone resorption and bone formation. Thus, the 15-PGDH inhibitors described herein can promote bone resorption and bone formation by inhibiting 15-PGDH activity. The 15-PGDH inhibitors may also be used to increase bone density, treat osteoporosis, promote fracture healing, or promote prognosis after skeletal surgery or joint replacement, or promote healing of bone and bone implants, bone and artificial implants, dental implants and bone grafts.

In other embodiments, the 15-PGDH inhibitor described herein is effective in treating a 15-PGDH-expressing cancer. Inhibition of 15-PGDH may inhibit the growth, proliferation and metastasis of cancers expressing 15-PGDH.

In other embodiments, the 15-PGDH inhibitors described herein can be used effectively for wound healing. Among the various prostaglandins, PGE is known₂Acting as a medium for wound healing. Thus, inhibition of 15-PGDH activity by PGE is achieved when the skin is damaged by a wound or burn₂Can be used for treating wound or burn.

Furthermore, as described above, increased levels of prostaglandins have been shown to stimulate signaling through the Wnt signaling pathway through increased β -chain protein mediated transcriptional activity. Wnt signaling is known to be an important pathway for the use of tissue stem cells. Thus, the 15-PGDH inhibitors described herein can be used to increase the number of tissue stem cells for a variety of purposes, including promoting tissue regeneration or organ (including liver, colon, and bone marrow) repair. In addition, the 15-PGDH inhibitors described herein can be used to promote tissue regeneration or repair of other organs, including but not limited to brain, eye, cornea, retina, lung, heart, stomach, small intestine, pancreas, pancreatic beta cells, kidney, bone, cartilage, peripheral nerves.

Syndromes, trauma, chronic disorders, medical interventions or other disorders that result in or are associated with tissue damage and require tissue repair, and thus are suitable for treatment or amelioration using the methods described herein, include, but are not limited to, acute coronary syndrome, Acute Lung Injury (ALI), Acute Myocardial Infarction (AMI), Acute Respiratory Distress Syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, sterile systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, cerebral edema, cerebral hypoperfusion, buerger's disease, burns, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced peripheral neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, peripheral neuropathy, chronic inflammation, vascular disease, vascular injury, Contusion, coronary heart disease (CAD), Critical Limb Ischemia (CLI), crohn's disease, deep venous thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetes, diabetic neuropathy, diabetes-induced ischemia, Disseminated Intravascular Coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, chilblain, hereditary hemorrhagic telangiectasia, hyperoxic injury, tissue hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injury, intermittent claudication, intestinal ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, placental ischemia, ischemic nephropathy, ischemic vascular disease, ischemic reperfusion injury, laceration, left trunk coronary heart disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, Osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, Peripheral Arterial Disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, precancerous, pulmonary edema, pulmonary embolism, remodeling disorders, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulceration, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, Transient Ischemic Attack (TIA), traumatic brain injury, ulcerative colitis, renal vascular disease, vascular inflammatory disorders, retinal vascular disease, and wounds to tissues or organs.

Other illustrative examples of genetic disorders, syndromes, trauma, chronic conditions, medical interventions or other conditions that cause or are associated with tissue damage and require tissue repair and that are suitable for treatment or amelioration using the methods of the invention include surgery, chemotherapy, radiation therapy or ischemia resulting from cell, tissue or organ transplantation or transplantation.

In various embodiments, the methods of the invention are useful for treating cerebrovascular ischemia, myocardial ischemia, limb ischemia (CLI), myocardial ischemia (particularly chronic myocardial ischemia), ischemic cardiomyopathy, cerebrovascular ischemia, renal ischemia, pulmonary ischemia, intestinal ischemia, and the like.

In some embodiments, the ischemia is associated with at least one of: acute coronary syndrome, Acute Lung Injury (ALI), Acute Myocardial Infarction (AMI), Acute Respiratory Distress Syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, aseptic systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, cerebral edema, cerebral hypoperfusion, Burger's disease, burn, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced peripheral neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary heart disease (CAD), Critical Limb Ischemia (CLI), Crohn's disease, deep venous thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, cerebral ischemia, cerebral, Ischemia caused by diabetes, Disseminated Intravascular Coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, hereditary hemorrhagic telangiectasia, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injury of the tendon, intermittent claudication, intestinal ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, placental ischemia, ischemic nephropathy, ischemic vascular disease, ischemia reperfusion injury, laceration, left trunk coronary heart disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, Peripheral Arterial Disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, precancerous, pulmonary edema, pulmonary embolism, remodeling disorder, renal ischemia, retinal ischemia, Retinopathy, sepsis, skin ulcers, solid organ transplantation, spinal cord injury, stroke, subchondral bone cysts, thrombosis, thrombotic cerebral ischemia, tissue ischemia, Transient Ischemic Attack (TIA), traumatic brain injury, ulcerative colitis, renovascular disease, vascular inflammatory disorders, retinal vascular neoplastic disease, and wounds to tissues or organs.

In some embodiments, the 15-PGDH inhibitor may be administered to a preparation of hematopoietic stem cells (e.g., peripheral blood hematopoietic stem cells or cord blood stem cells) of a subject, thereby increasing the fitness of the preparation of stem cells as a donor graft, or decreasing the number of units of cord blood required for transplantation.

Hematopoietic stem cells are pluripotent stem cells that produce all types of blood cells of the organism, including bone marrow lines (e.g., monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells) and lymphoid lines (e.g., T cells, B cells, NK cells), as well as those known in the art (see U.S. Pat. No. 5,635,387 to Fei, R. et al; U.S. Pat. No. 5,460,964 to McGlave et al; U.S. Pat. No. 5,677,136 to Simmons, P. et al; U.S. Pat. No. 5,750,397 to Tsukamoto et al; U.S. Pat. No. 5,759,793 to Schwartz et al; U.S. Pat. No. 5,681,599 to Diguistostostoto et al; U.S. Pat. No. 5,716,827 to Tsukamoto et al). Hematopoietic Stem Cells (HSCs) produce committed Hematopoietic Progenitor Cells (HPCs) that are capable of generating an intact mature blood cell pool that spans the lifetime of the organism.

Hematopoietic stem cells and hematopoietic progenitor cells are generally described herein as hematopoietic stem cells unless otherwise specified, and may be referred to by the antigenic marker CD34(CD 34)⁺) Is present in the identified cell or population. In some embodiments, hematopoietic stem cells may be identified by the presence of the antigenic marker CD34 and the absence of the lineage (lin) marker, and thus characterized as CD34⁺/lin^-A cell.

The hematopoietic stem cells used in the methods described herein can be obtained from any suitable source of hematopoietic stem cells and progenitor cells, and can be provided as a highly purified population of hematopoietic stem cells or a composition, wherein the composition comprises from about 0.01% to about 100% hematopoietic stem cells. For example, hematopoietic stem cells can be provided in a composition, such as unfractionated bone marrow (where the hematopoietic stem cells comprise less than about 1% of the population of bone marrow cells), umbilical cord blood, placental blood, placenta, fetal blood, fetal liver, fetal spleen, Wharton's jelly, or mobilized peripheral blood.

Suitable sources of hematopoietic stem cells may be isolated or obtained from a body organ containing cells of hematopoietic origin. Isolated cells may include cells removed from their original environment. A cell is isolated, for example, if it is separated from some or all of the components that normally accompany the cell in its natural state. For example, as used herein, an "isolated population of cells," "isolated source of cells," or "isolated hematopoietic stem cells" and the like, refers to one or more cells that are isolated from their native cellular environment and from their association with other tissue or organ components of interest (i.e., it is not significantly associated with in vivo material).

hematopoietic stem cells may be obtained or isolated from adult bone marrow, including femur, hip, ribs, sternum, and other bones. Bone marrow aspirate containing hematopoietic stem cells can be obtained directly or isolated from the buttocks using a needle and syringe. Other sources of hematopoietic stem cells include umbilical cord blood, placental blood, mobilized peripheral blood, wharton's jelly, placenta, fetal blood, fetal liver, or fetal spleen. In particular embodiments, harvesting a sufficient amount of hematopoietic stem cells for therapeutic use requires mobilization of donor stem and progenitor cells.

By "hematopoietic stem cell mobilization" is meant the release of stem cells from the bone marrow into the peripheral blood circulation for leukocyte depletion prior to stem cell transplantation. By increasing the number of stem cells harvested by a donor, the number of stem cells available for therapeutic use can be significantly improved. Hematopoietic growth factors, such as granulocyte colony stimulating factor (G-CSF) or chemotherapeutic agents are commonly used to stimulate mobilization. Commercially available stem cell mobilizing drugs are available and can be used in conjunction with G-CSF to mobilize sufficient numbers of hematopoietic stem and progenitor cells for transplantation into a subject. For example, G-CSF and Mozobil (Genzyme corporation) may be administered to a donor to harvest a sufficient number of hematopoietic cells for transplantation. Other methods of mobilizing hematopoietic stem cells will be apparent to any person having skill in the art.

In some embodiments, the Hematopoietic Stem and Progenitor Cells (HSPCs) are obtained from cord blood. Cord blood may be harvested according to techniques known in the art (see, e.g., U.S. patent nos. 7,147,626 and 7,131,958, the disclosure of which is hereby incorporated by reference).

In one embodiment, HSPCs may be derived from pluripotent stem cell sources, such as induced pluripotent stem cells (ipscs) and Embryonic Stem Cells (ESCs). As used herein, the term "induced pluripotent stem cell" or "iPSC" refers to a non-pluripotent cell that has been reprogrammed (reprogrammed) to a pluripotent state. Once a subject's cells are reprogrammed to a pluripotent state, the cells can be programmed to form a desired cell type, such as hematopoietic cells or progenitor cells. As used herein, the term "reprogramming" refers to a method of increasing the potential of a cell to a less differentiated state. As used herein, the term "programming" refers to a method of reducing the potential of a cell or differentiating a cell to a more differentiated state.

In some embodiments, one or more 15-PGDH inhibitors described herein can be administered to hematopoietic stem cells ex vivo or contacted with one or more 15-PGDH inhibitors described herein to provide a therapeutic composition. In one embodiment, the therapeutic composition may comprise a population of hematopoietic stem cells treated with one or more 15-PGDH inhibitors under ex vivo conditions. In certain embodiments, the therapeutic composition comprising enhanced HSPCs is whole bone marrow, cord blood, or mobilized peripheral blood.

In a specific embodiment, the therapeutic composition comprises a cell population, wherein the cell population is about 95% to about 100% hematopoietic stem cells. The present invention contemplates, in part, that the use of a therapeutic composition of highly purified hematopoietic stem cells (e.g., a composition comprising a population of cells, wherein the cells comprise about 95% hematopoietic stem cells) can improve the efficiency of stem cell therapy. Currently practiced transplantation methods typically use unfractionated cell mixtures, in which hematopoietic stem cells comprise less than 1% of the total cell population.

In some embodiments, the therapeutic composition comprises a cell population, wherein the cell population comprises less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% hematopoietic stem cells. In some embodiments, the population of cells comprises less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% hematopoietic stem cells. In other embodiments, the cell population is about 0.1% to about 1%, about 1% to about 3%, about 3% to about 5%, about 10% -15%, about 15% -20%, about 20% -25%, about 25% -30%, about 30% -35%, about 35% -40%, about 40% -45%, about 45% -50%, about 60% -70%, about 70% -80%, about 80% -90%, about 90% -95%, or about 95% to about 100% hematopoietic stem cells.

The hematopoietic stem cells in the therapeutic compositions of the invention may be autologous (autologous)/autotransplanted (autogeneic) ("self") or non-autologous ("non-self", e.g., allogeneic, syngeneic, or xenogeneic relative to the subject to whom the therapeutic composition is to be administered. As used herein, "autologous" refers to cells obtained from the same subject. As used herein, "heterologous" refers to a cell of the same species that is genetically distinct from the cell in comparison. As used herein, "syngeneic" refers to cells of a different subject that are genetically identical to the cells in comparison. As used herein, "xenogeneic" refers to cells of a different species than the cells in question.

Hematopoietic stem cells for use in the methods of the invention may be depleted mature hematopoietic cells such as T cells, B cells, NK cells, dendritic cells, monocytes, granulocytes, erythroid cells, and their committed precursors from bone marrow puncture, cord blood or mobilized peripheral blood (mobilized leukocyte depletion products). Mature lineage-committed cells are depleted by immunodepletion, for example by labelling a solid substrate with antibodies that bind to a set of so-called "lineage" antigens: CD2, CD3, CD11b, CD14, CD15, CD16, CD79, CD56, CD123, and CD235 a. Subsequent steps may be performed to further purify the cell population using CD34⁺Antigen-bound antibody-labeled substrates are used to isolate primary hematopoietic stem cells. Kits are commercially available for purification of stem and progenitor cells of various cell origins, and in particular embodiments, these kits are suitable for use in the methods of the invention.

in one embodiment, the amount of hematopoietic stem cells in the therapeutic composition is at least 0.1 x 10⁵Cells, at least 0.5X 10⁵cells, at least 1X 10⁵Cells, at least 5X 10⁵Cells, at least 10X 10⁵Cells, at least 0.5X 10⁶Cells, at least 0.75X 10⁶cells, at least 1X 10⁶Cells, at least 1.25X 10⁶Cells, at least 1.5X 10⁶Cells, at least 1.75X 10⁶Cells, at least 2X 10⁶Cells, at least 2.5X 10⁶Cells, at least 3X 10⁶Cells, at least 4X 10⁶Cells, at least 5X 10⁶Cells, at least 10X 10⁶Cells, at least 15X 10⁶Cells, at least 20X 10⁶Cells, at least 25X 10⁶Cells or at least 30X 10⁶A cell.

In one embodiment, in said treatment groupThe amount of hematopoietic stem cells in the composition is the amount of HSPC in a single cord blood (single cord of blood), or at least 0.1X 10⁵at least 0.5X 10 cells/kg body weight⁵At least 1X 10 cells/kg body weight⁵At least 5X 10 cells/kg body weight⁵At least 10X 10 cells/kg body weight⁵At least 0.5X 10 cells/kg body weight⁶At least 0.75X 10 cells/kg body weight⁶At least 1X 10 cells/kg body weight⁶At least 1.25X 10 cells/kg body weight⁶At least 1.5X 10 cells/kg body weight⁶At least 1.75X 10 cells/kg body weight⁶Cells/kg body weight, at least 2X 10⁶At least 2.5X 10 cells/kg body weight⁶Cells/kg body weight, at least 3X 10⁶At least 4X 10 cells/kg body weight⁶At least 5X 10 cells/kg body weight⁶At least 10X 10 cells/kg body weight⁶At least 15X 10 cells/kg body weight⁶At least 20X 10 cells/kg body weight⁶At least 25X 10 cells/kg body weight⁶cells/kg body weight, or at least 30X 10⁶Cells/kg body weight.

Hematopoietic stem cell preparations administered one or more 15-PGDH inhibitors and/or therapeutic compositions comprising hematopoietic stem cells and one or more 15-PGDH inhibitors may be used to improve hematopoietic stem cell transplantation and treat ischemic or ischemia damaged tissue, and reduce further damage to ischemic tissue and/or repair damage to ischemic tissue by cell recruitment, improve angiogenesis in ischemic tissue, improve tissue regeneration at the site of ischemia, reduce necrosis or apoptosis in ischemic tissue, and/or increase cell survival at the site of ischemia. In particular embodiments, a preparation of 15-PGDH inhibitor-treated hematopoietic stem cells and/or a therapeutic composition of a 15-PGDH inhibitor and hematopoietic stem cells may be used in a subject in need of hematopoietic reconstitution, e.g., a subject who has undergone or is scheduled to undergo myelosuppressive therapy.

Subjects that can be treated with a preparation of hematopoietic stem cells treated with a 15-PGDH inhibitor and/or a therapeutic composition of a 15-PGDH inhibitor and hematopoietic stem cells may include subjects who have, or have been diagnosed with, various types of leukemia, anemia, lymphoma, myeloma, immunodeficiency disorders, and solid tumors. Subjects also include humans who are candidates for stem cell transplantation or bone marrow transplantation, for example during malignant disease treatment or part of gene therapy. A subject may also include an individual or animal that donates stem cells or bone marrow for allogeneic transplantation. In certain embodiments, the subject may be undergoing myelosuppressive radiotherapy or chemotherapy, or may undergo acute radiation or chemical injury resulting in myelosuppression. In certain embodiments, the subject may be undergoing radiotherapy or chemotherapy, for example during the treatment of various cancers. Typical subjects include animals that exhibit an abnormal amount (lower or higher amount than a "normal" or "healthy" subject) of one or more physiological activities that can be modulated by an agent, stem cell or bone marrow transplantation.

Subjects that can be treated with the 15-PGDH inhibitor-treated preparation of hematopoietic stem cells and/or the 15-PGDH inhibitor and hematopoietic stem cell therapeutic composition can also include subjects undergoing chemotherapy or radiation therapy for cancer, as well as subjects suffering from (e.g., afflicted with) non-malignant blood disorders, particularly immunodeficiency (e.g., SCID, fanconi anemia, severe aplastic anemia, congenital hemoglobinopathy, or metabolic storage diseases, e.g., Hurler's disease, Hunter's disease, mannosidosis, etc.); or cancer, in particular hematologic malignancies, such as acute leukemia, chronic leukemia (myeloid or lymphoid), lymphoma (hodgkin or non-hodgkin), multiple myeloma, myelodysplastic syndrome, or non-hematologic cancers, such as solid tumors (including breast, ovarian, brain, prostate, lung, colon, skin, liver, or pancreatic cancer).

The subject may also include a subject suffering from aplastic anemia, an immune disorder (severe combined immunodeficiency syndrome or lupus), myelodysplasia, thalassemia, sickle cell anemia, or Wiskott-Aldrich syndrome. In some embodiments, the subject suffers from an undesirable side effect or complication resulting from another primary treatment, such as radiation therapy, chemotherapy, or treatment with a myelosuppressive drug (e.g., zidovudine, chloramphenicol, or ganciclovir). Such disorders include neutropenia, anemia, thrombocytopenia, and immune dysfunction. Other subjects may have a disorder (e.g., a viral infection, a bacterial infection, or a fungal infection) caused by an infection that results in damage to bone marrow stem cells or progenitor cells.

In addition, subjects suffering from the following conditions may also benefit from treatment with preparations of hematopoietic stem cells treated with a 15-PGDH inhibitor and/or therapeutic compositions of a 15-PGDH inhibitor and hematopoietic stem cells: lymphopenia, lymphatic fistula (lymphorrhea), lymphostasis, erythropenia, erythrodegenerative disorders, erythropenia, myelogenous anemia; erythrocyte fragmentation, thalassemia, myelodysplasia, myelofibrosis, thrombocytopenia, Disseminated Intravascular Coagulation (DIC), immune (autoimmune) thrombocytopenic purpura (ITP), HIV-induced ITP, myelodysplasia; thrombocythemia disease (thrombocytic disease), thrombocythemia, congenital neutropenia (e.g. Kostmann syndrome and Schwachman-Diamond syndrome), tumor-associated neutropenia, childhood and adult circulating neutropenia; neutropenia after infection; myelodysplastic syndrome; neutropenia associated with chemotherapy and radiotherapy; chronic granulomatous disease; mucopolysaccharide storage disease; burley-bubbly anemia; sickle cell anemia; or beta thalassemia.

In other embodiments, preparations of 15-PGDH inhibitor-treated hematopoietic stem cells and/or therapeutic compositions of 15-PGDH inhibitor and hematopoietic stem cells may be used in cell-based therapies to treat ischemic tissue or to treat or alleviate one or more symptoms associated with tissue ischemia, including, but not limited to, impaired or lost organ function (including, but not limited to, impairment or loss of brain, kidney, or heart function), cramping, claudication, numbness, tingling, weakness, pain, impaired wound healing, inflammation, skin discoloration, and gangrene.

In one embodiment, the subject exhibits at least one symptom of ischemic tissue or tissue damaged by ischemia. In particular embodiments, the subject is a human having or at risk of having ischemic tissue or tissue damaged by ischemia, e.g., a subject having diabetes, peripheral vascular disease, thromboangiitis obliterans, vasculitis, cardiovascular disease, coronary heart disease, heart failure, cerebrovascular disease, cardiovascular disease, or cerebrovascular disease.

Illustrative examples of genetic disorders, syndromes, trauma, chronic conditions, medical interventions or other conditions that result in or are associated with ischemia, or increase the risk of ischemia in a subject, or cause a subject to exhibit one or more symptoms of ischemia, and thus are suitable for treatment or alleviation using the methods described herein include, but are not limited to, acute coronary syndrome, Acute Lung Injury (ALI), Acute Myocardial Infarction (AMI), Acute Respiratory Distress Syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, sterile systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, brain edema, cerebral hypoperfusion, buerger's disease, burns, cancer, cardiovascular disease, cartilage injury, cerebral infarction, cerebral ischemia, cerebral stroke, cerebrovascular disease, chemotherapy-induced peripheral neuropathy, Chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, contusion, coronary heart disease (CAD), Critical Limb Ischemia (CLI), crohn's disease, deep venous thrombosis, deep wounds, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetic neuropathy, diabetes-induced ischemia, Disseminated Intravascular Coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, chilblain, hereditary hemorrhagic telangiectasia, hyperoxic injury, hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injured tendons, intermittent claudication, intestinal ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, placental ischemia, ischemic nephropathy, ischemic vascular disease, ischemia reperfusion injury, laceration, left trunk coronary heart disease, Limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, Peripheral Arterial Disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, precancerous, pulmonary edema, pulmonary embolism, remodeling disorders, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulceration, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, Transient Ischemic Attack (TIA), traumatic brain injury, ulcerative colitis, renal angiopathy, vascular inflammatory disorders, retinal angiomatosis, and wounds to tissues or organs.

Other illustrative examples of genetic disorders, syndromes, trauma, chronic conditions, medical interventions or other conditions that result in or are associated with ischemia, or increase the risk of ischemia in a subject, or that result in a subject exhibiting one or more symptoms of ischemia and that are suitable for treatment or alleviation using the methods described herein include ischemia resulting from surgery, chemotherapy, radiation therapy, or cell, tissue or organ transplantation or graft.

In various embodiments, the present invention contemplates that the therapeutic cell compositions disclosed herein can be used to treat ischemic tissue where it is desirable to increase blood flow, oxygen supply, glucose supply, or nutrient supply to the tissue.

In some embodiments, the 15-PGDH inhibitor may be administered to a preparation of tissue stem cells (e.g., neural stem cells, mesenchymal stem cells, or stem cells that can give rise to other tissues) and/or a preparation of pluripotent stem cells.

In one embodiment, the tissue stem cells may be derived from a pluripotent stem cell source, such as induced pluripotent stem cells (ipscs) and Embryonic Stem Cells (ESCs). As used herein, the term "induced pluripotent stem cell" or "iPSC" refers to a non-pluripotent cell that has been reprogrammed to form a pluripotent state. Once a subject's cells are reprogrammed to a pluripotent state, the cells can be programmed to form a desired cell type, such as hematopoietic cells or progenitor cells. As used herein, the term "reprogramming" refers to a method of increasing the potential of a cell to a less differentiated state. As used herein, the term "programming" refers to a method of reducing the potential of a cell or differentiating a cell to a more differentiated state.

In some embodiments, one or more 15-PGDH inhibitors described herein can be administered to tissue stem cells and/or pluripotent stem cells ex vivo or contacted with one or more 15-PGDH inhibitors described herein to provide a therapeutic composition. In one embodiment, the therapeutic composition may comprise a population of tissue stem cells treated with one or more 15-PGDH inhibitors under ex vivo conditions.

In a specific embodiment, the therapeutic composition comprises a cell population, wherein the cell population is about 95% to about 100% tissue stem cells. The present invention contemplates, in part, that the use of therapeutic compositions of highly differentiated tissue stem cells (e.g., compositions comprising a population of cells, wherein the cells comprise about 95% tissue stem cells) can improve the efficiency of stem cell therapy.

In some embodiments, the therapeutic composition comprises a cell population, wherein the cell population comprises less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% tissue stem cells. In some embodiments, the population of cells comprises less than about 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% tissue stem cells. In other embodiments, the cell population is about 0.1% to about 1%, about 1% to about 3%, about 3% to about 5%, about 10% -15%, about 15% -20%, about 20% -25%, about 25% -30%, about 30% -35%, about 35% -40%, about 40% -45%, about 45% -50%, about 60% -70%, about 70% -80%, about 80% -90%, about 90% -95%, or about 95% to about 100% tissue stem cells.

The tissue stem cells in the therapeutic compositions of the invention can be autologous/autografted ("autologous") or non-autologous ("non-autologous", e.g., allogeneic, syngeneic, or xenogeneic) relative to the subject to which the therapeutic composition is to be administered. As used herein, "autologous" refers to cells obtained from the same subject. As used herein, "heterologous" refers to a cell of the same species that is genetically distinct from the cell in comparison. As used herein, "syngeneic" refers to cells of a different subject that are genetically identical to the cells in comparison. As used herein, "xenogeneic" refers to cells of a different species than the cells in question.

Tissue stem cell preparations administered with one or more 15-PGDH inhibitors and/or therapeutic compositions comprising tissue stem cells and one or more 15-PGDH inhibitors may be used to improve tissue stem cell transplantation and treat damaged tissue, and reduce further tissue damage to the tissue and/or enhance repair of damaged tissue by stem cell recruitment, and/or increase cell survival at the site of tissue damage.

Syndromes, trauma, chronic conditions, medical interventions or other conditions which result in or are associated with tissue damage and require tissue repair and thus are suitable for treatment or alleviation using the methods described herein include, but are not limited to, acute coronary syndrome, Acute Lung Injury (ALI), Acute Myocardial Infarction (AMI), Acute Respiratory Distress Syndrome (ARDS), arterial occlusive disease, arteriosclerosis, articular cartilage defects, sterile systemic inflammation, atherosclerotic cardiovascular disease, autoimmune disease, bone fracture, cerebral edema, cerebral hypoperfusion, buerger's disease, burns, cancer, cardiovascular disease, cartilage damage, cerebral infarction, cerebral ischemia, stroke, cerebrovascular disease, chemotherapy-induced peripheral neuropathy, chronic infection, chronic mesenteric ischemia, claudication, congestive heart failure, connective tissue injury, Contusion, coronary heart disease (CAD), Critical Limb Ischemia (CLI), crohn's disease, deep venous thrombosis, deep wound, delayed ulcer healing, delayed wound healing, diabetes (type I and type II), diabetes, diabetic neuropathy, diabetes-induced ischemia, Disseminated Intravascular Coagulation (DIC), embolic cerebral ischemia, graft-versus-host disease, chilblain, hereditary hemorrhagic telangiectasia, hyperoxic injury, tissue hypoxia, inflammation, inflammatory bowel disease, inflammatory disease, injury, intermittent claudication, intestinal ischemia, ischemic brain disease, ischemic heart disease, ischemic peripheral vascular disease, placental ischemia, ischemic nephropathy, ischemic vascular disease, ischemic reperfusion injury, laceration, left trunk coronary heart disease, limb ischemia, lower limb ischemia, myocardial infarction, myocardial ischemia, organ ischemia, Osteoarthritis, osteoporosis, osteosarcoma, Parkinson's disease, Peripheral Arterial Disease (PAD), peripheral arterial disease, peripheral ischemia, peripheral neuropathy, peripheral vascular disease, precancerous, pulmonary edema, pulmonary embolism, remodeling disorders, renal ischemia, retinal ischemia, retinopathy, sepsis, skin ulceration, solid organ transplantation, spinal cord injury, stroke, subchondral bone cyst, thrombosis, thrombotic cerebral ischemia, tissue ischemia, Transient Ischemic Attack (TIA), traumatic brain injury, ulcerative colitis, renal vascular disease, vascular inflammatory disorders, retinal vascular disease, and wounds to tissues or organs.

Other illustrative examples of genetic disorders, syndromes, trauma, chronic conditions, medical interventions or other conditions which result in or are associated with tissue damage and require tissue repair and which are suitable for treatment or alleviation using the methods described herein include surgery, chemotherapy, radiation therapy, or ischemia resulting from cell, tissue or organ transplantation or graft.

in various embodiments, the methods of the invention are useful for treating cerebrovascular ischemia, myocardial ischemia, limb ischemia (CLI), myocardial ischemia (particularly chronic myocardial ischemia), ischemic cardiomyopathy, cerebrovascular ischemia, renal ischemia, pulmonary ischemia, intestinal ischemia, and the like.

In other embodiments, the 15-PGDH inhibitor may be administered to a bone marrow transplant donor or a hematopoietic stem cell donor, thereby increasing the fitness of the donor bone marrow transplant or the donor hematopoietic stem cell transplant.

In other embodiments, the 15-PGDH inhibitor may also be administered to bone marrow of a subject, thereby increasing stem cells of the subject, or increasing the fitness of bone marrow as a donor graft.

in other embodiments, the 15-PGDH inhibitor may be administered to a subject, thereby reducing bone marrow graft rejection, enhancing bone marrow graft engraftment, enhancing engraftment of a hematopoietic stem cell graft or an umbilical cord blood stem cell graft, and/or reducing the number of units of umbilical cord blood required for transplantation into the subject. The administration may be, for example, after treatment of the subject or bone marrow of the subject with radiation therapy, chemotherapy, or immunosuppressive therapy.

In other embodiments, the 15-PGDH inhibitor may be administered to a recipient of a bone marrow transplant, hematopoietic stem cell transplant, umbilical cord blood stem cell transplant, thereby reducing the administration of other therapies or growth factors.

In some embodiments, the 15-PGDH inhibitor may be administered to a subject, thereby increasing neutrophil recovery following bone marrow transplantation, following cord blood transplantation, following hematopoietic stem cell transplantation, following traditional chemotherapy, following radiation therapy, in neutropenic individuals (resulting from diseases including, but not limited to, aplastic anemia, myelodysplasia, myelofibrosis, neutropenia caused by other myelopathies, drug-induced neutropenia, immune neutropenia, idiopathic neutropenia), and following viral (including, but not limited to, HIV, CMV, and parvovirus) infection.

In other embodiments, the 15-PGDH inhibitor may be administered to a subject, thereby increasing recovery of platelets following bone marrow transplantation, following cord blood transplantation, following hematopoietic stem cell transplantation, following traditional chemotherapy, following radiation therapy, in neutropenic individuals (resulting from diseases including, but not limited to, aplastic anemia, myelodysplasia, myelofibrosis, thrombocytopenia caused by other bone marrow diseases, drug-induced thrombocytopenia, immune thrombocytopenia, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenia), and following viral (including, but not limited to, HIV, CMV, and parvovirus) infection.

In other embodiments, the 15-PGDH inhibitor may be administered to a subject to increase hemoglobin recovery after bone marrow transplantation, after cord blood transplantation, after hematopoietic stem cell transplantation, after traditional chemotherapy, after radiation therapy, in anemic individuals (resulting from diseases including, but not limited to, aplastic anemia, myelodysplasia, myelofibrosis, anemia arising from other bone marrow diseases, drug-induced anemia, immune-mediated anemia, anemia of chronic disease, idiopathic anemia), and after viral (including, but not limited to, HIV, CMV, and parvovirus) infection.

In some embodiments, the 15-PGDH inhibitor may be administered to a subject, thereby increasing the number of bone marrow stem cells in a bone marrow transplant, a cord blood transplant, a hematopoietic stem cell transplant, a traditional chemotherapy, a radiation therapy, other bone marrow disease individuals, a cytopenia individual following a viral infection, and a cytopenia individual.

In other embodiments, the 15-PGDH inhibitor may be administered to a subject, thereby increasing the response to cytokines administered to an individual with cytopenia, including but not limited to neutropenia, thrombocytopenia, lymphopenia and anemia. Cytokines whose response can be enhanced by SW033291 include, but are not limited to, G-CSF, GM-CSF, EPO, IL-3, IL-6, TPO, SCF, and TPO-RA (thrombopoietin receptor agonist).

In other embodiments, the 15-PGDH inhibitor may be administered to a subject or a tissue transplant of a subject, thereby reducing transplant rejection following radiation therapy, chemotherapy, or immunosuppressive therapy, enhancing transplant implantation, enhancing implantation of a bone marrow transplant of a subject or subject, conferring resistance to toxic or lethal effects of exposure to radiation, conferring resistance to toxic effects of cyclophosphamide, fludarabine, chemotherapy, or immunosuppressive therapy, reducing infection, and/or reducing radiation-induced pulmonary toxicity.

In other embodiments, the 15-PGDH inhibitor may be administered to a recipient of tissue stem cell transplantation, including but not limited to hematopoietic stem cell transplantation, neural stem cell transplantation, mesenchymal stem cell transplantation, stem cell transplantation for other tissues, to accelerate tissue regeneration and repair after transplantation.

In some embodiments, administration of a 15-PGDH inhibitor may be combined with G-CSF for the purpose of increasing neutrophils.

in other embodiments, administration of the 15-PGDH inhibitor may be combined with a hematopoietic cytokine for the purpose of increasing neutrophils.

In other embodiments, administration of the 15-PGDH inhibitor may be combined with G-CSF for the purpose of increasing the number of and/or mobilizing peripheral blood hematopoietic stem cells.

In some embodiments, administration of the 15-PGDH inhibitor may be combined with a second agent (including plerixafor) for the purpose of increasing the number of and/or mobilizing peripheral blood hematopoietic stem cells.

In other embodiments, administration of the 15-PGDH inhibitor may be combined with G-CSF for the purpose of increasing the number of peripheral blood hematopoietic stem cells used for hematopoietic stem cell transplantation and/or mobilizing peripheral blood hematopoietic stem cells.

In other embodiments, administration of the 15-PGDH inhibitor may be combined with a hematopoietic cytokine for the purpose of increasing the number of peripheral blood hematopoietic stem cells used for hematopoietic stem cell transplantation and/or mobilizing peripheral blood hematopoietic stem cells.

In other embodiments, administration of the 15-PGDH inhibitor may be combined with a second agent (including plerixafor) for the purpose of increasing the number of and/or mobilizing peripheral blood hematopoietic stem cells for hematopoietic stem cell transplantation.

In other embodiments, administration of the 15-PGDH inhibitor may be combined with G-CSF in order to increase the number of hematopoietic stem cells in the blood or bone marrow.

In other embodiments, the 15-PGDH inhibitors are useful for treating and/or preventing fibrosis and various fibrotic diseases, disorders or conditions, and reducing fibrotic symptoms, such as collagen deposition, inflammatory cytokine expression, and inflammatory cell infiltration.

In some embodiments, a method of preventing a fibrotic disease, disorder or condition comprises administering to a subject in need thereof a therapeutically effective amount of a 15-PGDH inhibitor such that at least one symptom or feature of the fibrotic disease, disorder or condition, or other related disease, disorder or condition, is reduced in intensity, severity, or frequency, or has delayed onset.

As used herein, the term "fibrotic" disease, disorder or condition includes diseases, disorders or conditions characterized in whole or in part by overproduction of fibrotic material (including overproduction of fibrotic material in extracellular matrix) or replacement of normal tissue elements by abnormal non-functional and/or excessive accumulated matrix-related components. Fibrotic diseases, disorders or conditions may include acute and chronic clinical or subclinical manifestations, where the biological or pathological aspects associated with fibrogenesis are evident.

Examples of fibrotic diseases, disorders and conditions include systemic sclerosis, multifocal fibrosclerosis, renal systemic fibrosis, scleroderma (including scleroderma, generalized scleroderma or linear scleroderma), graft-versus-host disease of scleroderma, nephrofibrosis (including glomerulosclerosis, tubulointerstitial fibrosis, progressive renal disease or diabetic nephropathy), cardiac fibrosis (e.g., cardiomyopathy), pulmonary fibrosis (e.g., glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease and chemotherapy/radiotherapy-induced pulmonary fibrosis), oral fibrosis, myocardial endocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, crohn's disease, necrotizing fasciitis, eosinophilic inflammation, fibrosis syndrome in general (characterized by the unequal replacement of normal muscle tissue by fibrous tissue), Retroperitoneal fibrosis, hepatic fibrosis, chronic interstitial hepatitis, chronic renal failure; myelofibrosis (myelofibrosis), drug-induced ergotoxemia, glioblastoma in the plum-fomeni syndrome, sporadic glioblastoma, myelogenous leukemia, acute myelogenous leukemia, myelodysplastic syndrome, myeloproliferative syndrome, gynecological tumors, kaposi's sarcoma, hansens disease, collagenous colitis, acute fibrosis, specific organ fibrosis, etc.

Exemplary organ-specific fibrotic disorders include, but are not limited to, pulmonary fibrosis, pulmonary hypertension, cystic fibrosis, asthma, chronic obstructive pulmonary disease, hepatic fibrosis, renal fibrosis, NASH, and the like. Many fibrotic diseases, disorders or conditions have disorganized and/or excessive extracellular matrix deposition in the affected tissue. Fibrosis may be associated with inflammation, occur as an underlying disease symptom, and/or result from surgical procedures or wound healing processes. Unchecked fibrosis can lead to destruction of underlying organ or tissue structural systems, commonly referred to as scarring.

In some embodiments, the 15-PGDH inhibitor is useful for treating or preventing pulmonary fibrosis. Pulmonary fibrosis may be selected from pulmonary fibrosis, pulmonary hypertension, Chronic Obstructive Pulmonary Disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal mineworker's pneumoconiosis, charcoal pneumoconiosis, hypersensitivity pneumonitis, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by infectious agents, pulmonary fibrosis caused by inhalation of toxic gases, aerosols, chemical dusts, smoke or vapors, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof.

Pulmonary fibrosis is characterized by progressive scarring of the lung tissue with fibrocyte proliferation, excessive accumulation of extracellular matrix proteins, and abnormal alveolar structure. Thickened and stiff tissue makes it difficult for the lungs to work properly, resulting in respiratory problems, such as shortness of breath, and can ultimately be fatal. Pulmonary fibrosis may result from acute lung injury, viral infection, exposure to toxins, radiation, chronic disease, drugs, or may be idiopathic (i.e., an undiscovered underlying cause).

The classic findings of idiopathic pulmonary fibrosis show diffuse peripheral scarring of the lung with small vesicles (called pulmonary bullae) adjacent to the outer lining of the lung surface (usually at the base of the lung). Idiopathic pulmonary fibrosis usually has a slow and ongoing progression. Early, patients often complained of dry cough of unknown origin. Subsequently, hypopnea begins (dyspnea) and over time, deterioration is triggered by the lower and lower activity. Eventually, shortness of breath becomes a disability, limits all activity, and even occurs when standing still. In more rare cases, fibrosis can progress rapidly and dyspnea and disability occur within weeks to months of disease onset. This form of pulmonary fibrosis is known as the Hamman-Rich syndrome (Hamman-Rich syndrome).

Pulmonary hypertension is marked by elevated pulmonary vascular blood pressure, including pulmonary arteries, pulmonary veins, and/or pulmonary capillaries. Abnormal high pressure strains the right ventricle of the heart, causing it to dilate. Over time, the right ventricle may weaken and lose its ability to pump sufficient blood to the lungs, resulting in the development of heart failure. The development of other medical conditions can lead to pulmonary hypertension, such as chronic liver disease and chronic interstitial hepatitis; rheumatic disorders, such as scleroderma or systemic lupus erythematosus (lupus); pulmonary disorders including tumors, emphysema, Chronic Obstructive Pulmonary Disease (COPD), and pulmonary fibrosis. Pulmonary fibrosis can lead to narrowing of the pulmonary vessels, leading to pulmonary hypertension.

Chronic Obstructive Pulmonary Disease (COPD) is a common lung disease that is often associated with chronic bronchitis or emphysema. Symptoms may typically include cough, mucus formation, fatigue, wheezing and respiratory infections.

Chronic bronchitis and emphysema are lung diseases in which the airways become narrowed. This results in a restricted inflow and outflow of air from the lungs, resulting in shortness of breath (dyspnea). In clinical practice, COPD is defined as low airflow characteristic of pulmonary function testing.

Lung injury and inflammation of the large airways lead to chronic bronchitis. In the airways of the lung, chronic bronchitis is marked by an increase in the number (hyperplasia) and size (hypertrophy) of airway goblet cells and mucous glands. As a result, the airway is more viscous than usual, causing the airway to narrow and resulting in coughing and sputum. Under the microscope, the airway wall is infiltrated with inflammatory cells. Scarring and remodeling occur after inflammation, which thickens the airway wall and also causes the airway to narrow. With the progression of chronic bronchitis, there is squamous metaplasia (abnormal changes in the tissue lining the inside of the airways) and fibrosis (further thickening of the airway wall and scarring). The result of these changes is a restricted airflow and difficulty in breathing.

Asthma is a chronic lung disease characterized by airway inflammation and contraction. Asthma causes recurrent periods of wheezing, chest tightness, shortness of breath and cough. Swelling and excessive production of mucus can further lead to airway constriction and worsening of symptoms. Evidence is that increased matrix degradation can occur in asthma and may contribute to mechanical changes in the airways in asthma (Roberts et al (1995) Chest 107:111S-117S, which is incorporated herein by reference in its entirety).

Cystic fibrosis is a recessive multisystemic genetic disease characterized by abnormal transport of chloride and sodium across epithelial cells, resulting in thickened, viscous secretions of the lung, pancreas, liver, intestine and reproductive tract. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Pulmonary disease is caused by airway obstruction due to mucus formation, decreased mucociliary clearance, and resultant inflammation, which can lead to fibrotic damage and structural changes in the lung. Fibrotic lung injury develops over a period of time, resulting in the need for lung transplantation in some patients with cystic fibrosis.

General symptoms of subjects with cystic fibrosis include, but are not limited to, accumulation of mucus, production of sputum, frequent chest infections, frequent coughs, frequent shortness of breath, inflammation, reduced mobility, opportunistic infections of the lung and sinuses (including, but not limited to, staphylococcus aureus (staphyloccocus aureus), Haemophilus influenzae (Haemophilus influenzae), Mycobacterium avium (Mycobacterium avium) and pseudomonas aeruginosa), pneumonia, tuberculosis, bronchiectasis, hemoptysis, pulmonary hypertension (and resulting heart failure), hypoxia, respiratory failure, allergic bronchopulmonary aspergillosis, mucus in the paranasal sinuses, paranasal sinus infections, facial neuralgia, fever, excessive nasal drainage, development of nasal polyps, cardiopulmonary complications, CF-related diabetes, rectal prolapse, pancreatitis, malabsorption, intestinal obstruction, exocrine pancreatic secretion, and intestinal obstruction, Bile duct obstruction and chronic interstitial hepatitis.

In other embodiments, the 15-PGDH inhibitor may be used to treat or prevent a fibrotic disease, disorder or condition caused by post-surgical adhesion formation. Post-surgical adhesion formation is a common complication of surgery. Adhesions formed by mechanical injury, ischemia, and infection can increase postoperative morbidity and mortality. Although delicate surgical procedures can reduce the extent of adhesion formation, adhesions are rarely resected and require effective adjuvant therapy. Reducing fibrosis associated with this procedure can reduce pain, blockage and other complications of surgery and promote healing and recovery.

Wounds (i.e., tears, openings) in mammalian tissue lead to tissue destruction and microvascular coagulation of the wound surface. Repair of such tissues suggests an orderly controlled cellular response to injury. Soft tissue wounds heal in a similar manner regardless of size. Tissue growth and repair is a biological system in which cell proliferation and angiogenesis occur in the presence of an oxygen gradient. The successive morphological and structural changes that occur during tissue repair have been characterized in detail and, in some cases, quantified (see, for example, Hunt, T.K., et al, "diagnosis and mapping of angiogenesis and surrounding health," in The scientific Wund, pp.1-18, ed.F. dineen & G. Hildrick-Smith (Lea & Febiger, Philadelphia: 1981)). Cell morphology consists of 3 distinct regions. The central avascular wound space (central avascular wound space) is oxygen deficient, acidotic and hypercarbonated (hypercarbic) and has high lactate levels. Adjacent to the wound space is a gradient region of ischemia, which is occupied by dividing fibroblasts. Following the leader region is an active collagen synthesis zone characterized by mature fibroblasts and a large number of newly formed capillaries (i.e., neovascularization). U.S. patent nos. 5,015,629 and 7,022,675 (both incorporated herein by reference) disclose methods and compositions for increasing the rate of wound repair.

In some embodiments, the 15-PGDH inhibitor can be used to reduce or prevent scarring in a subject by administering to a subject in need of treatment. Scarring is a natural part of the healing process. Disordered collagen synthesis and deposition at the wound site can lead to excessive, thickened or increased scarring. Generally, the larger the wound, the longer it takes to heal, and the higher the chance of forming a problematic scar.

In other embodiments, the 15-PGDH inhibitor can be used to reduce or prevent scarring of skin or scleroderma. There are various types of scars on the skin. Hypertrophic scarring increases in the reddish regions located inside the boundaries of the original lesion. They are often described as itchy. In some cases, hypertrophic scars shrink and recede themselves. Keloids increase in the deep red areas, which tend to cover a larger area than the original lesion. Keloids often recur even when removed surgically. Atrophic scars are depressions in the skin similar to those typically formed by severe acne. They are caused by inflammation, which destroys collagen during remodeling, resulting in recessed areas.

in some embodiments, the 15-PGDH inhibitor is useful for treating or preventing systemic sclerosis. Systemic sclerosis is a systemic connective tissue disease characterized by microvascular changes, immune system disorders, and the massive deposition of collagen and other matrix materials in connective tissue. Systemic sclerosis is a clinically heterogeneous generalized disorder that affects the connective tissue of the skin and internal organs, such as the gastrointestinal tract, lungs, heart and kidneys. Reducing fibrosis caused by systemic sclerosis may alleviate symptoms and/or prevent other complications in the affected tissue.

In other embodiments, the 15-PGDH inhibitor is useful for treating or preventing liver fibrosis. Hepatic fibrosis may be caused by chronic liver disease, post-hepatitis cirrhosis, hepatitis b virus infection, hepatitis c virus infection, hepatitis d virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis obesity, diabetes, protein malnutrition, coronary heart disease, autoimmune hepatitis, cystic fibrosis, alpha-1-antitrypsin deficiency, primary biliary cirrhosis, drug reactions and exposure to toxins.

Nonalcoholic steatohepatitis (NASH) is a common liver disease. It is similar to alcoholic liver disease, but occurs in persons who drink little or no alcohol. The main feature of NASH is fat in the liver, along with inflammation and injury. NASH, however, can be severe and can lead to cirrhosis, in which the liver is permanently damaged and scarred and can no longer function properly.

NASH is typically a silent disease with little or no symptoms. Patients often feel well in the early stages and begin to have only symptoms such as fatigue, weight loss, or weakness once the disease has progressed further or cirrhosis has developed. The process of NASH can be years, even decades. The process may be stopped and in some cases may even begin reversing itself without specific treatment. Or NASH can slowly deteriorate, leading to the appearance or accumulation of scarring or fibrosis in the liver. As fibrosis worsens, cirrhosis progresses, wherein the liver becomes severely scarred, stiffened and does not function properly. Not everyone with NASH develops cirrhosis, but once severe scarring or cirrhosis exists, few treatments can prevent this process. People with cirrhosis experience fluid retention, muscle atrophy, intestinal bleeding, and liver failure. Liver transplantation is the only treatment for late-stage cirrhosis with liver failure, and is increasingly performed in people with NASH. In america, NASH is ranked as one of the major causes of cirrhosis after hepatitis c and alcoholic liver disease.

In some embodiments, the 15-PGDH inhibitor is useful for treating or preventing renal fibrosis. Renal fibrosis can be caused by renal failure, catheter placement, nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal insufficiency, acute renal injury, end stage renal disease, or dialysis after renal failure.

Renal (kidney) fibrosis is caused by an excess formation of fibrous connective tissue in the kidney. Renal fibrosis causes significant morbidity and mortality, and results in the need for dialysis or kidney transplantation. Fibrosis can develop in the filtering or reabsorbing part of the nephron (the functional unit of the kidney). A variety of factors can contribute to renal scarring, particularly physiological disorders associated with autoregulation of glomerular filtration. This will in turn lead to the replacement of normal structures by accumulated extracellular matrix. The spectrum of changes in the physiology of individual cells leads to the production of a variety of peptide and non-peptide fibrogens (fibrigens) that stimulate a change in the balance between extracellular matrix synthesis and degradation, thereby favoring scar formation.

In some embodiments, the symptoms of fibrosis of the tissue organ may include inflammation. In these embodiments, administering a therapeutically effective amount of a 15-PGDH inhibitor to a subject in need thereof may be an amount effective to reduce or decrease inflammatory cell count in a tissue or organ. A relevant sample can be obtained from the subject, thereby determining a decrease or decrease in inflammatory cell count. In non-limiting embodiments, a beneficial effect can be assessed by demonstrating a decrease in neutrophil count in BAL fluid from a cystic fibrosis subject. Excessive recruitment of neutrophils to the airways of CF patients is a clear predictor of the severity of pulmonary disease by CF and is therefore an important therapeutic target. Methods for measuring such cell counts are well known in the art, including but not limited to FACS counting. In some embodiments, the method may comprise reducing the count of neutrophils in BAL fluid obtained from the subject as compared to a control. Any suitable control can be used for comparison, e.g., cystic fibrosis subjects not treated with a 15-PGDH inhibitor. In some embodiments, a decrease in inflammatory cell count (e.g., neutrophil count) provides a clinical benefit to the subject. In various embodiments, the inflammatory cell count is reduced by at least 5%, 10%, 15%, 20%, 25%, 50% or more compared to a control.

in another embodiment, the beneficial effect of a 15-PGDH inhibitor may be assessed by a decrease in one or more inflammatory biomarkers in a relevant sample from the subject. In various non-limiting embodiments, the inflammatory biomarker can include or consist of one or more cytokines or inflammatory cytokines associated with fibrosis. Such cytokines may include, for example, IL1 β, MIP2 (e.g., CCL3 or CCL4), IFN δ, TGF β, TNF α, IL-6, MCP-1, IL2, and IL-10 in BAL fluid. Methods for measuring the amount of such biomarkers are well known in the art, including but not limited to ELISA. Thus, in such embodiments, the method may further comprise reducing the amount of one or more inflammatory biomarkers in the sample obtained from the subject as compared to a control.

In other embodiments, the 15-PGDH inhibitor may be used in a method of reducing or decreasing collagen secretion or collagen deposition in a tissue or organ (e.g., lung, liver, skin, or heart) of a subject. The method can comprise administering to a subject in need thereof a therapeutically effective amount of a 15-PGDH inhibitor. The subject may have or be at risk of excessive collagen secretion or collagen deposition in a tissue or organ, such as kidney, lung, liver, intestine, colon, skin or heart. Usually, excessive collagen secretion or collagen deposition in organs is caused by injury or damage. Such injuries and lesions are organ-specific. The 15-PGDH inhibitor may be administered for a sufficient period of time to completely or partially reduce or reduce the level of collagen deposition in the tissue or organ. Sufficient time periods may be 1 week, 1 week to 1 month, 1 month to 2 months, 2 months or more. For chronic conditions, 15-PGDH inhibitors may be advantageously administered for life.

Inhibitors of 15-PGDH for treating fibrotic diseases, disorders or conditions and/or reducing collagen deposition can be identified using an assay in which a putative inhibitor compound is applied to cells expressing 15-PGDH and the functional effect on 15-PGDH activity is then determined. The degree of effect is examined by comparing a sample or test containing 15-PGDH treated with a potential inhibitor with a control sample without the inhibitor. Control samples (not treated with modulator) were assigned a relative 15-PGDH activity value of 100%. Inhibition of 15-PGDH is obtained when the 15-PGDH activity value relative to the control is about 80%, and optionally 50% or 25%, 10%, 5% or 1%.

Furthermore, in model organisms, PGE2 signaling stimulates liver regeneration and increases survival after exposure to hepatotoxic agents (e.g., acetaminophen). Thus, the 15-PGDH inhibitors described herein may be used to increase liver regeneration after liver resection (in other contexts, including after liver surgery, after liver donation, or after receiving liver transplantation), or to increase liver regeneration and increase survival after exposure to hepatotoxic agents, including but not limited to acetaminophen and similar compounds.

PGE1 analogs have also been used to treat erectile dysfunction. Thus, in some embodiments, the 15-PGDH inhibitors described herein can be used alone or in combination with prostaglandins for the treatment of erectile dysfunction.

The 15-PGDH inhibitors described herein may also be used to promote neuroprotection from axonal degeneration following injury, neuronal cell death and/or glial cell injury, enhance neuronal signaling for learning and memory, stimulate neuronal regeneration following injury, and/or treat diseases, disorders and/or conditions of the nervous system in a subject.

In some embodiments, a disease, disorder, and/or condition of the nervous system that can be treated with the 15-PGDH inhibitor can include at least one of a neurological disorder, a neuropsychiatric disorder, a nerve injury, a neurotoxic disorder, neuropathic pain, and a neurodegenerative disorder.

In some embodiments, the 15-PGDH inhibitors described herein are useful in methods of treating (e.g., controlling, ameliorating, reducing, or slowing the progression of) or preventing (e.g., delaying onset or reducing the risk of progression of) one or more diseases, disorders, or conditions caused by or associated with insufficient neurogenesis (e.g., abnormal) or undesired neuronal cell death in a subject in need thereof. The method comprises administering to the subject an effective amount of a 15-PGDH inhibitor described herein (and/or a compound having any other formula described herein) or a salt (e.g., a pharmaceutically acceptable salt) as defined in any part herein. The one or more diseases, disorders, or conditions may include neuropathy, neurotrauma, and neurodegenerative diseases.

In some embodiments, the one or more diseases, disorders or conditions may be a disease, disorder or condition caused by or associated with under-neurogenesis believed to occur in neuropsychiatric diseases (e.g., abnormal hippocampal neurogenesis), or abnormal neuronal cell death believed to occur in neurodegenerative diseases. Examples of the one or more diseases, disorders, or conditions include, but are not limited to, schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, parkinson's disease, alzheimer's disease, down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, huntington's chorea, stroke, radiation therapy, chronic stress, and abuse of neuroactive drugs, such as alcohol, opioids, methamphetamine, phencyclidine, and ***e.

in some embodiments, the subject may be a subject in need thereof (e.g., a subject identified as in need of such treatment, e.g., a subject having or at risk of having one or more diseases or disorders described herein). Identifying a subject in need of such treatment can be at the discretion of the subject or a healthcare professional, and can be subjective (e.g., opinion) or objective (e.g., measurable by testing or diagnostic methods). In some embodiments, the subject may be a mammal. In certain embodiments, the subject may be a human.

In other embodiments, the 15-PGDH inhibitors may be used to treat diseases, disorders, or conditions associated with nervous system elements (elements of the nervous system), including central, somatic, autonomic, sympathetic, and parasympathetic components of the nervous system, neurosensory tissue within the eye, ear, nose, mouth, or other organs, and glial tissue associated with neuronal cells and structures. Neurological disorders may be caused by neuronal damage, e.g. mechanical damage or damage caused by toxic compounds, by abnormal growth or development of neurons, or by mis-regulation, e.g. down-regulation of neuronal activity.

Neurological disorders can have adverse effects on nervous system functions, such as sensory function (ability to perceive changes in the body and external environment); general function (ability to interpret changes); and motor functions (in response to interpreted abilities by initiating actions such as muscle contraction or glandular secretion).

Examples of neurological disorders that can be treated by administering a 15-PGDH inhibitor to a subject in need thereof include traumatic or toxic injury to the peripheral or cranial nerves, the spinal cord, or to the brain, cranial nerves, traumatic brain injury, stroke, cerebral aneurysm, and spinal cord injury. Other neurological disorders that can be treated by administering a 15-PGDH inhibitor to a subject in need thereof include alzheimer's disease, dementia associated with alzheimer's disease (such as pick's disease), parkinson's disease and other diffuse body diseases of the lewy body, senile dementia, huntington's disease, gilles de la tourette's syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy (Charcot-Marie-Tooth disease), diabetic neuropathy, progressive supranuclear palsy, epilepsy or jacobia-creutzfeldt-jakob disease. Autonomic dysfunction includes hypertension and sleep disorders.

Also treated with the 15-PGDH inhibitors described herein are neuropsychiatric disorders such as depression, schizophrenia, schizoaffective disorders, Korsakoff's psychosis (Korsakoff s psychosis), mania, anxiety or phobias, learning or memory disorders (such as amnesia and age-related memory loss), attention deficit disorder, mood disorders (dynamic disorders), major depression, mania, obsessive compulsive disorder, psychoactive substance use disorders (psychoactive substance disorders), anxiety disorders, phobias, panic disorders, bipolar disorders, psychoactive pain syndrome and eating disorders. Other examples of neurological disorders that can be treated by administering a 15-PGDH inhibitor to a subject in need thereof include neurological damage due to infectious diseases, such as meningitis, high fever of various etiologies, HIV, syphilis, or post-polio syndrome (post-polio syndrome), and neurological damage due to electrical currents, including contact with electricity or lightning, and complications from electroconvulsive psychiatric treatment. Neurological disorders associated with ophthalmic conditions include retinal and optic nerve damage, glaucoma and age-related macular degeneration.

The developing brain is a target for neurotoxicity in the developing central nervous system during many stages of pregnancy as well as during infancy and childhood, and the 15-PGDH inhibitors described herein are useful for preventing or treating neurological deficits in intrauterine embryos or fetuses, premature infants or children in need of such treatment, including children with nervous system birth defects. Other neurological DISORDERS include, for example, those listed in HARRISON 'S PRINCIPLES OF INTERNAL MEDICINE (Braunwald et al, McGraw-Hill,2001) and in AMERICAN PSYCHIATRIC ASSOCIATION' S DIAGNOSTIC STAND STATISTICAL MANUAL OF MEDICAL DISORDERS DSM-IV (American Psychiatric Press, 2000).

The 15-PGDH inhibitors described herein are also useful in methods of treating medical conditions associated with nerve damage. Medical condition may refer to any movement disorder, epilepsy, cerebrovascular disease, autoimmune disease, sleep disorder, autonomic nervous disorder, bladder disorder, abnormal metabolic state, muscular system disorder, infectious disease and parasitic disease, tumor, endocrine disease, nutritional and metabolic disease, immune disease, blood and hematopoietic organ disease, mental disorder, nervous system disease, sensory organ disease, circulatory system disease, respiratory system disease, digestive system disease, genitourinary system disease, skin and subcutaneous tissue disease, musculoskeletal system and connective tissue disease, congenital abnormality, certain conditions of perinatal origin, and conditions of undefined symptoms and signs.

Treatable cerebrovascular diseases may result from conditions including, but not limited to, aneurysm, stroke, arrhythmia, myocardial infarction, ischemia reperfusion injury, and cerebral hemorrhage.

treatable autoimmune diseases include, but are not limited to, multiple sclerosis.

Sleep disorders treatable by 15-PGDH inhibitors may result from conditions including, but not limited to, sleep apnea and sleep abnormality (parasomnias).

Autonomic disorders treatable by a 15-PGDH inhibitor may result from conditions including, but not limited to, gastrointestinal motility disorders, nausea, vomiting, diarrhea, chronic hiccup, gastroesophageal reflux disease, excessive gastric acid secretion, autonomic dysfunction; excessive epiphora (excessive epiphora), excessive rhinorrhea; and cardiovascular diseases including, but not limited to, cardiac arrhythmias and arrhythmias, hypertension, and carotid sinus disease.

Bladder disorders that can be treated by 15-PGDH inhibitors can result from conditions including, but not limited to, spinal cord injury and spastic or flaccid bladder.

Abnormal metabolic states treatable by 15-PGDH inhibitors may result from conditions including, but not limited to, hyperthyroidism or hypothyroidism.

Disorders of the muscular system that can be treated by a 15-PGDH inhibitor may include, but are not limited to, muscular dystrophy, and spasticity of the upper respiratory tract and face.

The 15-PGDH inhibitors may also be used to treat neuropathic pain resulting from conditions including, but not limited to, migraine including migraine with aura, migraine without aura, migraine in the menstrual period, migraine variants, atypical migraine, complex migraine, hemiplegic migraine, transition migraine and chronic daily migraine, paroxysmal tension headache, chronic tension headache, analgesic rebound headache, paroxysmal cluster headache, chronic cluster headache, cluster variation, chronic paroxysmal half headache, persistent half headache, post-traumatic neck pain, post-herpetic neuralgia involving the head or face, spinal fracture pain secondary to osteoporosis, spinal arthritic pain, headache associated with cerebrovascular disease and stroke, headache resulting from vascular disease, reflex sympathetic dystrophy, Neck pain (which may be due to a variety of causes including, but not limited to, muscular, discogenic or degenerative, including arthritic, posture-related or metastatic), tongue pain, carotid pain, annular cartilaginous pain (cricoiodynia), ear pain due to middle ear pathology, stomach pain, sciatica, maxillary neuralgia, laryngalgia, cervical musculodynia, trigeminal neuralgia (sometimes also known as painful tic (tic douroureux)), post-lumbar puncture headache, low cerebrospinal fluid pressure headache, temporomandibular joint disorder, atypical facial pain, ciliary neuralgia, parasympathetic neuralgia (sometimes also known as Raeder syndrome); lithostegia, eggle's syndrome, idiopathic intracranial hypertension, orofacial pain, myofascial pain syndrome involving the head, neck and shoulders, chronic migraine neuralgia, cervical headache, parasympathetic trigeminal paralysis, SPG neuralgia (sometimes also referred to as lower-half headache, lower-face neuralgia syndrome, studer's neuralgia, and druder's headache), carotid artery, vidoesophageal headache (vidian headaches), causalgia, and/or combinations thereof.

As used herein, the term "headache" can refer to migraine, tension headache, cluster headache, trigeminal neuralgia, secondary headache, tension headache, chronic and persistent headache, drug overuse/rebound headache, chronic paroxysmal hemicrania (chronic paropsymal hemicrania headaches), hemicephalic persistent headache (hemicrania headaches), post-traumatic headache, post-herpetic headache, vascular headache, reflex sympathetic dystrophy-related headache, crvicalgia headache, carolidonia headache, sciatica, trigeminal headache, occipital headache, maxillary bone headache, daily headache (heart headaches), accessory nerve headache, lithologic headache (petrosal headaches), srudder head pain, vidus headache, low headache pressure headache, TMCSF headache, causalgia, myofascial headache, all primary headache (e.g., primary, secondary headache, tension headache, chronic and headache, Primary headache, primary headache associated with sexual activity, sleep headache (hypnic headache) and new, daily persistent headache), all trigeminal idiopathic headaches (e.g., paroxysmal hemicephalic (epidyssomal hemicranias), SUNCT, all possible TAC and SUNA), chronic daily headache, occipital neuralgia, atypical facial pain, neuropathic trigeminal neuralgia and headaches of various types.

In other embodiments, the 15-PGDH inhibitor may be used to promote survival, plasticity, and/or growth of neural stem cells or progenitor cells. The 15-PGDH inhibitor may be administered to the stem or progenitor cells ex vivo, in vitro or in vivo. When administered ex vivo or in vitro to stem or progenitor cells, the stem or progenitor cells can then be transplanted into a subject for therapeutic use.

For example, for neural stem/progenitor cells, a method of transplanting neural stem/progenitor cells to a desired area commonly used in the field of regenerative medicine may be used in combination with administration of a 15-PGDH inhibitor to the cells or area. More specifically, a method of transplanting neural stem/progenitor cells to a region of interest, for example, by: suspending neural stem/progenitor cells in phosphate buffered saline containing a 15-PGDH inhibitor; and the resulting cell suspension is added/injected to the area.

In other embodiments, the 15-PGDH inhibitors described herein can be applied to nerve grafts. The implant may comprise any tissue for implantation in a human or animal body. Various types of grafts are included in the present invention, such as autografts, allografts (syngrafts), allografts and xenografts. The size (e.g., length and diameter) of the graft is not critical. For example, the nerve graft may be about 1 cm to about 10 cm in length, or more than about 10 cm in length. The diameter of the nerve graft may be matched to any damaged nerve or portion of a nerve, as desired. The nerve graft may be a structurally intact nerve segment to bridge a gap or replace a distal end along the length of the recipient nerve, i.e., for end-to-end grafting. Alternatively, the nerve graft may be part of a nerve segment or eccentric shape (e.g., a nerve flap), and is intended to reconstruct a torn nerve with some structural disruption but still maintain its physical continuity.

When the 15-PGDH inhibitor is applied to a nerve graft, the entire graft can be treated. The therapeutic agent may be applied to the entire nerve graft as a whole. The whole-piece treatment can be applied to a living (fresh) or previously frozen nerve graft. The therapeutic agent may also be administered to the nerve graft before, during, or after implantation. The therapeutic agent may be applied to any portion of the graft, such as one or more ends that are attached to the stump of the damaged nerve. If the therapeutic agent is applied to the damaged nerve, the therapeutic agent may be applied to any area of the damaged nerve that promotes repair of the damaged nerve, such as at or near the site of the injury.

The 15-PGDH inhibitor may be placed in a medium for nerve grafts, which may be a natural medium, a defined medium, or a defined medium, e.g., supplemented with serum. Embodiments described herein also include a storage solution for storing a nerve graft prior to implantation. The storage solution contains a culture medium and at least one 15-PGDH inhibitor. The storage solution may also contain other bioactive agents, such as growth factors described below.

It is understood that other 15-PGDH inhibitors may be used in the methods of the invention. These other 15-PGDH inhibitors may include known 15-PGDH inhibitors, including tetrazole compounds of formulae (I) and (II), 2-alkyleneaminooxyacetamide compounds of formula (I), heterocyclic compounds of formulae (VI) and (VII), and pyrazole compounds of formula (III), for example, as described in U.S. patent application publication No. 2006/0034786 and U.S. patent No. 7,705,041; a benzylidene-1, 3-thiazolidine compound represented by the formula (I) described in U.S. patent application publication No. 2007/0071699; phenylfurylmethyl thiazolidine-2, 4-dione and phenylthienylmethyl thiazolidine-2, 4-dione compounds described in U.S. patent application publication No. 2007/0078175; thiazolidinedione derivatives described in U.S. patent application publication No. 2011/0269954; a phenylfuran, phenylthiophene or phenylpyrrole compound described in U.S. Pat. No. 7,294,641; 5- (3, 5-disubstituted phenylazo) -2-hydroxyphenyl-acetic acids and salts, and lactones as described in U.S. patent No. 4,725,676; azo compounds described in U.S. patent No. 4,889,846; and 15-PGHD inhibitors described in PCT/US2014/060761 and U.S. patent application publication No. 2015/0072998a1, all of which are incorporated by reference herein in their entirety.

The 15-PGDH inhibitors described herein may be provided in a pharmaceutical or cosmetic composition, depending on the pathological or cosmetic condition or disorder to be treated. Pharmaceutical compositions comprising a 15-PGDH inhibitor as described herein as an active ingredient may be manufactured by mixing the derivative with one or more pharmaceutically acceptable carriers or excipients, or diluting the 15-PGDH inhibitor with a diluent according to conventional methods. The pharmaceutical composition may further comprise fillers, anti-adherents, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives and the like. The pharmaceutical composition may be formulated into a suitable formulation according to methods known to those skilled in the art such that it may provide immediate, controlled or sustained release of the 15-PGDH inhibitor after administration to a mammal.

In some embodiments, the pharmaceutical composition may be formulated in parenteral or oral form. Solid dosage forms for oral administration may be manufactured by adding excipients (if desired) together with binders, disintegrants, lubricants, colorants and/or flavors to the 15-PGDH inhibitor and forming the resulting mixture into the form of tablets, sugar-coated pills, granules, powders or capsules. The additives that may be added to the composition may be those conventional in the art. Examples of excipients include, for example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicates, and the like. Exemplary binders include water, ethanol, propanol, sweet syrup, sucrose solutions, starch solutions, gelatin solutions, carboxymethyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphonate, and pyrrolidone. Examples of the disintegrating agent include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, and lactose. Furthermore, pure talc, stearates, sodium borate and polyethylene glycol can be used as lubricants; and sucrose, bitter orange peel, citric acid, tartaric acid can be used as flavoring agent. In some embodiments, the pharmaceutical compositions may be formulated as a spray formulation for administration by inhalation (e.g., they may be nebulized).

The 15-PGDH inhibitors described herein may be combined with flavoring agents, buffers, stabilizers, and the like, and incorporated into oral liquid dosage forms, such as solutions, syrups, or elixirs, according to conventional methods. An example of a buffer may be sodium citrate. Examples of stabilizers include tragacanth, acacia, and gelatin.

In some embodiments, the 15-PGDH inhibitors described herein can be introduced into injectable dosage forms, e.g., for subcutaneous, intramuscular, or intravenous routes, by adding pH modifiers, buffers, stabilizers, relaxants, local anesthetics thereto. Examples of pH adjusters and buffers include sodium citrate, sodium acetate, and sodium phosphate. Examples of stabilizers include sodium metabisulfite, EDTA, thioglycolic acid and thiolactic acid. The local anesthetic can be procaine HCl, lidocaine HCl, etc. The relaxant may be sodium chloride, glucose, etc.

In other embodiments, the 15-PGDH inhibitors described herein may be formulated into suppositories according to conventional methods by adding thereto pharmaceutically acceptable carriers known in the art (if necessary), such as polyethylene glycol, lanolin, cocoa butter or fatty acid glycerides, together with a surfactant (e.g., Tween).

The pharmaceutical compositions may be formulated in a variety of dosage forms as discussed above and then administered by a variety of routes including oral, inhalation, transdermal, subcutaneous, intravenous or intramuscular routes. The dosage may be a pharmaceutically effective amount. The pharmaceutically effective amount can be an amount of a 15-PGDH inhibitor for treating or ameliorating hair loss, cardiovascular disease, gastrointestinal disease, wound and kidney disease. The pharmaceutically effective amount of the compound will be appropriately determined depending on the kind and severity of the disease to be treated, the age, sex, body weight and physical condition of the patient to be treated, the route of administration, the duration of treatment and the like. Generally, an effective amount of a compound may be about 1 to 1,000mg in oral administration, about 0.1 to 500mg in intravenous administration, and about 5 to 1,000mg in rectal administration. Generally, the daily dose for an adult is about 0.1 to 5,000mg, preferably about up to 1,000mg, but cannot be defined in general because it depends on the age, sex, body weight and physical condition of the patient to be treated. The formulation may be administered in divided doses once or more times per day.

Cosmetic compositions comprising a 15-PGDH inhibitor may comprise any substance or preparation which will bring them into contact with the various surface parts of the human body (epidermis, hair and hair system, nails, lips and external genitalia) or with the teeth or buccal mucosa, the specific or primary purpose of which is to clean them, perfume them, alter their appearance and/or correct body odour and/or protect them or keep them in a good condition.

The cosmetic composition may comprise a cosmetically acceptable medium, which may be water, or a mixture of water and at least one solvent selected from: hydrophilic organic solvents, lipophilic organic solvents, amphoteric organic solvents, and mixtures thereof.

For topical application, the cosmetic composition may be applied by: aqueous, alcoholic, water-alcohol or oily solutions or suspensions; or in a lotion or dispersion of serotypes; in emulsions, which have a liquid or semi-liquid consistency, or are pasty; can be obtained by dispersing the fatty phase in the aqueous phase (O/W) or vice versa (W/O) or in various emulsions; dispersed or compacted powders used as such or introduced into physiologically acceptable media; other microcapsules or microparticles; or a dispersion of vesicles of ionic and/or non-ionic type. Thus, it may be in the form of an ointment, tincture, emulsion, cream, salve, powder, patch, pad, solution, emulsion, vesicle dispersion, lotion, aqueous or anhydrous gel, spray, suspension, shampoo, aerosol, or foam. It may also be a solid preparation constituting a soap or cleansing bar.

The cosmetic composition may in particular comprise a hair care composition, in particular a shampoo, a styling lotion, a therapeutic lotion, a styling cream or gel, a reconstituted lotion of the hair, a mask, etc. The cosmetic composition may be a cream, a hair lotion, a shampoo or a conditioner. These may be used specifically in treatments using the use described (which may or may not be rinsed thereafter), or in other shampoo forms. Compositions in the form of foams, or in the form of sprays or aerosols (which contain a propellant under pressure) are also contemplated. Thus, it may be in the form of a lotion, serum, lotion, cream, gel, salve, ointment, powder, balm, patch, pad, block, or foam.

In particular, the composition for the scalp or hair may be in the form of a hair care lotion, for example for use once a day or twice a week; shampoo or conditioner forms, in particular, twice weekly or once weekly use; liquid or solid soap for cleaning scalp, used once a day; hair styling products (hair gels, hair styling products or styling gels); a treatment mask; a foam gel or cream for cleansing hair. They may also be hair dyes or dye pastes applied with a brush or comb.

Furthermore, for topical application to the eyelashes or body hair, the composition may be in the form of a pigmented or unpigmented mascara for application to the eyelashes using a brush, or alternatively to the beard or beard. For administration of the composition by injection, the composition may be in the form of an aqueous alkenyl or oily suspension. For oral use, the composition may be in the form of a capsule, a granule, an oral syrup, or a tablet. According to a particular embodiment, the composition is in the form of a hair cream or lotion, a shampoo, a conditioner or a mascara for the hair or eyelashes.

In a known manner, the cosmetic composition may also comprise adjuvants common in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, fragrances, fillers, UV-screening agents, deodorants and dyes. The amounts of these various adjuvants are those conventionally used in the cosmetic field, for example from 0.1% to 20% by weight, in particular less than or equal to 10% by weight of the total composition. Depending on the nature of the adjuvant, these adjuvants may be introduced into the fat phase, into the aqueous phase and/or into the lipid globules.

In some embodiments, the 15-PGDH inhibitor may be administered in a combination therapy or combination therapy, wherein the therapy comprises administration of the 15-PGDH inhibitor, together with one or more additional active agents. The phrases "combination therapy" or "combination therapy" encompass the administration of a 15-PGDH inhibitor and one or more therapeutic agents as part of a particular treatment regimen, which is expected to provide a potent effect from the combined action of these therapeutic agents. The combined administration of these therapeutic agents is typically carried out over a defined period of time (typically minutes, hours, days or weeks depending on the combination selected). "combination therapy" or "combination therapy" is intended to encompass the administration of these therapeutic agents in a continuous manner, wherein each therapeutic agent is administered at a different time; and at least 2 of these therapeutic agents or therapeutic agents are administered in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dose of each therapeutic agent in a fixed ratio or multiple administrations of each therapeutic agent as a single dose. Sequential or substantially simultaneous administration of the various therapeutic agents may be by any suitable route, including but not limited to oral route, intravenous route, intramuscular route, and direct absorption through mucosal tissue. The therapeutic agents may be administered by the same route or by different routes. The order of administration of the therapeutic agents is not particularly critical.

In some embodiments, the additional active agent may be specifically selected from lipoxygenase inhibitors described in EP 648488; bradykinin inhibitors described in particular in EP 845700; prostaglandins and derivatives thereof, in particular those described in WO98/33497, WO 95/11003, JP 97-100091, JP 96-134242; agonists or antagonists of prostaglandin receptors, and non-prostanoid analogs of prostaglandins, as described in EP 1175891 and EP 1175890, WO 01/74307, WO 01/74313, WO 01/74314, WO 01/74315, or WO 01/72268.

In other embodiments, the 15-PGDH inhibitor may be administered in combination with an active agent, such as a vasodilator, a prostanoid agonist, an antiandrogen, a cyclosporin or an analog thereof, a bactericide, a triterpene, or a mixture thereof, alone. Vasodilators may include potassium channel agonists including minoxidil and its derivatives, amanits molecules and compounds described in U.S. patent nos. 3,382,247, 5,756,092, 5,772,990, 5,760,043, 5,466,694, 5,438,058, 4,973,474, chromakalin and chlorothiazide. Antiandrogens may include 5. alpha. -reductase inhibitors such as finasteride and the compounds described in U.S. patent No. 5,516,779, cyproterone acetate, azelaic acid and salts and derivatives thereof, the compounds described in U.S. patent No. 5,480,913, flutamide and the compounds described in U.S. patent nos. 5,411,981,5,565,467 and 4,910,226. The antimicrobial compounds may include selenium derivatives, ketoconazole, triclocarban, triclosan, zinc pyrithione, itraconazole, pyridine acid, hinokitiol, mipirocine, compounds described in EP 680745, clindamycin hydrochloride, benzoyl or benzyl peroxide, and minocycline. Anti-inflammatory agents may include specific inhibitors of Cox-2, such as NS-398 and DuP-697(B.Batistini et al, DN & P1994; 7(8): 501-511); and/or inhibitors of lipoxygenase, particularly 5-lipoxygenase, such as zileuton (F.J.Alvarez & R.T.Slade, Pharmaceutical Res.1992; 9(11): 1465-.

Other active compounds that may be present in the pharmaceutical and/or cosmetic compositions may include meienis molecules and derivatives thereof, 60- [ (9Z,12Z) octadeca-9, 12-dienoyl ] hexopyranose, algaecide, benzethonium chloride, phenol, oestradiol, chlorpheniramine, chlorophyllin derivatives, cholesterol, cysteine, methionine, benzyl nicotinate, methanol, peppermint oil, calcium pantothenate, panthenol, resorcinol, protein kinase C inhibitors, prostaglandin H synthase 1 or COX-1 activators, COX-2 activators, glycosidase inhibitors, mucopolysaccharide inhibitors, pyroglutamate, hexose or acylhexonic acids, substituted vinylaryl, N-acylated amino acids, flavonoids, derivatives and analogs of ascomycin, histamine antagonists, triterpenes (such as ursolic acid and those described in U.S. Pat. No. 5,529,769, derivatives of ascomycin, derivatives of alpha-hydroxy acids, beta-hydroxy acids, Compounds described in us patent No. 5,468,888 and us patent No. 5,631,282), saponins, proteoglycan enzyme inhibitors, agonists and antagonists of estrogens, pseudopeptides, cytokine and growth factor promoters, IL-1 or IL-6 inhibitors, IL-10 promoters, TNF inhibitors, vitamins (e.g., vitamin D), analogs of vitamin B12, panthenol, hydroxy acids, benzophenones, esterified fatty acids, and hydantoins.

The pharmaceutical and/or cosmetic composition comprising the 15-PGDH inhibitor according to the invention may additionally comprise, for example, at least one compound selected from: prostaglandins, in particular prostaglandin PGE₁、PGE₂Their salts, their esters, their analogs and their derivatives, in particular those described in WO98/33497, WO 95/11003, JP 97-100091, JP 96-134242, in particular agonists of the prostaglandin receptor. It may in particular comprise at least one compound, such as an agonist (in acid form or in precursor form, in particular in ester form) of the prostaglandin F2 alpha receptor, such as latanoprost, fluprostenol, chloroprostenol, bimatoprost, unoprostone; agonists of prostaglandin E2 receptors (and their precursors, especially esters, e.g. travoprost), e.g. 17-phenyl PGE₂viprostenol, butaprost, misoprostol, sulprostone, 16-dimethyl PGE₂11-deoxy PGE₁1-deoxy PGE₁(ii) a Agonists of prostacyclin (IP) receptors and their precursors, especially esters, such as cicaprost, iloprost, isocarbacyline, beraprost, epostenol, treprostinil; agonists of prostaglandin D2 receptor and their precursors, in particular esters, such as BW245C ((4S) - (3- [ (3R, S) -3-cyclohexyl-3-isopropyl)]-2, 5-dioxo) -4-imidazolidinoheptanoic acid), BW246C ((4R) - (3- [ (3R, S) -3-cyclohexyl-3-isopropyl)]-2, 5-dioxo) -4-imidazolidinoheptanoic acid); agonists of the thromboxane A2(TP) receptor and their precursors, in particular esters, such as I-BOP ([1S- [1a,2a (Z),3b (1E,3S),4a]]-7- [3- [ 3-hydroxy-4- [4- (iodophenoxy) -1-butenyl radical]-7-oxabicyclo- [2.2.1]Hept-2-yl]-5-heptenoic acid).

Advantageously, the composition may comprise at least one 15-PGDH inhibitor as defined above, and at least one prostaglandin or one prostaglandin derivative, for example a series 2 prostaglandin, including in particular PGF in saline or in precursor form_2αAnd PGE₂Especially esters (e.g. isopropyl esters) and their derivatives, e.g. 16, 16-dimethyl PGE₂17-phenyl PGE₂And 16, 16-dimethyl PGF_2α17-phenyl PGF_2α(ii) a Prostaglandins of series 1, such as 11-deoxyprostaglandin E1, 1-deoxyprostaglandin E1, in the form of physiological saline or in the form of precursors, their analogues, in particular latanoprost, travoprost, fluprostenol, unoprostone, bimatoprost, chloroprostenol, vicprostenol, butaprost, misoprostol, their salts or their esters.

The invention is further illustrated by the following examples, which are not intended to limit the scope of the claims.

Examples

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