Use of PPAR-delta agonists in the treatment of mitochondrial myopathy
阅读说明：本技术 PPAR-δ激动剂在治疗线粒体肌病中的用途 (Use of PPAR-delta agonists in the treatment of mitochondrial myopathy ) 是由 科林·奥卡罗尔 尼尔·奥唐奈 林恩·普尔金斯 亚历克斯·多伦鲍姆 于 2020-02-20 设计创作，主要内容包括：本文描述了PPARδ激动剂在治疗线粒体肌病中的用途。在一方面,本文描述了用于治疗哺乳动物的原发性线粒体肌病(PMM)的方法,包括向患有原发性线粒体肌病的哺乳动物施用过氧化物酶体增殖物激活受体δ(PPARδ)激动剂化合物。在另一方面,本文描述了在患有原发性线粒体肌病的哺乳动物中调节PPARδ的方法,包括向患有原发性线粒体肌病的哺乳动物施用PPARδ激动剂化合物。(Described herein is the use of PPAR δ agonists in the treatment of mitochondrial myopathy. In one aspect, described herein is a method for treating a Primary Mitochondrial Myopathy (PMM) in a mammal comprising administering a peroxisome proliferator activated receptor delta (PPAR δ) agonist compound to a mammal having a primary mitochondrial myopathy. In another aspect, described herein is a method of modulating PPAR δ in a mammal having a primary mitochondrial myopathy, comprising administering a PPAR δ agonist compound to a mammal having a primary mitochondrial myopathy.)
1. A method for treating a primary mitochondrial myopathy in a mammal, comprising administering a peroxisome proliferator-activated receptor delta (PPAR δ) agonist compound to the mammal having the primary mitochondrial myopathy.
2. The method of claim 1, wherein:
treating the primary mitochondrial myopathy comprises increasing oxidative phosphorylation (OXPHOS) in the mammal, improving exercise tolerance, improving muscle histology, improving mitochondrial DNA copy number, improving the level of heterogeneity, improving mitochondrial mass, reducing pain, reducing fatigue, improving cognition, improving overall health, increasing survival, or a combination thereof in the mammal.
3. The method of claim 1 or claim 2, wherein:
the PPAR δ agonist compound is administered to a mammal in an amount sufficient to increase OXPHOS ability in the mammal, up-regulate gene expression of any one of the enzymes or proteins involved in OXPHOS, or a combination thereof.
4. The method of any one of claims 1-3, wherein:
the PPAR δ agonist compound is administered to the mammal in an amount sufficient to increase Fatty Acid Oxidation (FAO) capacity in the mammal, up-regulate gene expression of any one of the enzymes or proteins involved in FAO, or a combination thereof.
5. The method of any one of claims 1-4, wherein the mammal having primary mitochondrial myopathy has:
-at least one mutation or deletion in at least one mitochondrial dna (mtdna) gene;
-at least one mitochondrial dna (mtdna) defect;
-at least one mutation or deletion in at least one nuclear dna (ndna) gene involved in mitochondrial function; or
-combinations thereof.
6. The method of claim 5, wherein:
the at least one mutation in the at least one mitochondrial DNA (mtDNA) gene comprises a mutation selected from the group consisting of m.3243A > G, m.8344A > G, m.8993T > G, m.13513G > A, m.11778G > A, m.14484T > C, and combinations thereof.
7. The method of claim 5, wherein:
the at least one mutation in at least one mitochondrial DNA (mtDNA) gene comprises a mutation selected from the group consisting of an 8284bp deletion, a 6277bp deletion, a 4977bp deletion, and combinations thereof.
8. The method of claim 5, wherein:
the at least one mutation or deletion in at least one nuclear DNA (nDNA) gene involved in mitochondrial function includes at least one mutation or deletion in the nDNA gene encoding complex I (NADH: ubiquinone oxidoreductase), complex II (succinate dehydrogenase), complex III (CoQ-cytochrome c reductase), complex IV (cytochrome c oxidase), complex V (ATP synthase), aminoacyl-tRNA synthetase, release factor, elongation factor, mitochondrial ribosomal protein, thiamine, and phosphate, or a combination thereof.
9. The method of claim 8, wherein:
the gene encoding the compound I comprises NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NDUFA1, NDUFA2, NDUFA9, NDUFA10, NDUFA11, NDUFA12, NDUFA13, NDUFAF2, NDUFAF6 or NDUFB 11;
the gene encoding complex II comprises SDHA, SDHB, SDHC, SDHD or SDHAF 1;
the gene encoding complex III comprises UQCRB, BCS1L, UQCRQ, UQCRC2, CYC1, TTC19, LYRM7, UQCC2, or UQCC 3;
the gene encoding compound IV comprises COA5, SURF1, COX10, COX14, COX15, COX20, COX6B1, FASTKD2, SCO1, SCO2, LRPRC, TACO1 or PET 100;
the gene encoding complex V comprises ATPAF2, TMEM70, ATP5E, or ATP5a 1;
the genes encoding aminoacyl-tRNA synthetases include AARS2, DARS2, EARS2, RARS2, YARS2, FARS2, HARS2, LARS2, VARS2, TARS2, IARS2, CARS2, PARS2, NARS2, KARS, GARS, SARS2, or MARS 2;
the gene encoding a release factor includes C12orf 65;
the gene encoding an elongation factor comprises TUFM, TSFM or GFM 1;
the genes encoding mitochondrial ribosomal proteins include MRPS16, MRPS22, MRPL3, MRP12, or MRPL 44; and is
The genes encoding the solute carriers of thiamine and phosphate include SLC19A3, SLC25A3, or SLC25A 19.
10. The method of claim 5, wherein:
the at least one mutation or deletion in at least one nuclear dna (nDNA) gene involved in mitochondrial function includes at least one mutation or deletion in the nDNA gene involved in phospholipid metabolism, toxic compound metabolism, disulfide-relay systems, ferritin assembly, tRNA modification, mRNA processing, mitochondrial fusion or fission, deoxynucleotide triphosphate synthesis, protein quality control and degradation, ATP and ADP transport, or a combination thereof.
11. The method of claim 10, wherein:
the genes involved in phospholipid metabolism include AGK, SERAC1 or TAZ;
the genes involved in toxic compound metabolism include HIBCH, ECHS1, ETHE1 or MPV 17;
the genes involved in the disulfide relay system include GFER;
the genes involved in ferrothionein assembly include ISCU, BOLA3, NFU1, or IBA 57;
the genes involved in tRNA modification include MTO1, GTP3BP, TRMU, PUS1, MTFMT, TRIT1, TRNT1, or TRMT 5;
the genes involved in mRNA processing include LRPRC, TACO1, ELAC2, PNPT1, HSD17B10, MTPAP or PTCD 1;
the genes involved in mitochondrial fusion and fission comprise OPA1 or MFN 2;
the genes involved in deoxynucleotide triphosphate synthesis include DGUOK, TK2, TYMP, MGME1, SUCLG1, SUCLA2, RNASEH1, C10orf2, POLG2, DNA2, or RRM 2B;
the genes involved in protein quality control and degradation include FBXL4, AFG3L2, or SPG 7; and is
The genes involved in ATP and ADP transport include ANT 1.
12. The method of any one of claims 1 to 11, wherein:
the mammal has been diagnosed with Kearns-Sayre syndrome (KSS), Leigh syndrome, Maternally Inherited Leigh Syndrome (MILS), mitochondrial DNA depletion syndrome (MDS), mitochondrial encephalomyopathy, lactic acidosis and stroke-like attacks (MELAS), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with fragmented red fibers (MERRF), Neurological Ataxia and Retinitis Pigmentosa (NARP), Pearson syndrome, or progressive extraocular Paralysis (PEO).
13. The method of any one of claims 1-12, wherein:
the mammal having the primary mitochondrial myopathy further comprises a secondary mitochondrial myopathy.
14. The method of claim 13, wherein:
wherein the secondary mitochondrial myopathy comprises a secondary defect in OXPHOS function caused by the primary FAO defect, or the secondary mitochondrial myopathy is caused by a primary OXPHOS deficiency leading to a secondary FAO disease.
15. The method of any one of claims 1-14, wherein the PPAR δ agonist compound increases mitochondrial biogenesis.
16. The method of any one of claims 1-15, wherein the PPAR δ agonist compound increases the expression or activity of a gene or protein involved in mitochondrial biogenesis.
17. The method of claim 16, wherein the protein is peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1 a).
18. The method of any one of claims 1-17, wherein the PPAR δ agonist compound increases the expression or activity of a gene involved in oxidative phosphorylation or a protein thereof.
19. The method of any one of claims 1-18, wherein the PPAR δ agonist compound increases the percentage of the proportion of non-mutated mitochondrial dna (mtDNA) relative to mutated mtDNA.
20. The method of any one of claims 1-19, wherein:
the PPAR δ agonist compounds bind to and activate the cellular PPAR δ and do not substantially activate the cellular peroxisome proliferator-activated receptor α (PPAR α) and the cellular peroxisome proliferator-activated receptor γ (PPAR γ).
21. The method of any one of claims 1-20, wherein:
the PPAR δ agonist compound is a phenoxyalkylcarboxylic acid compound.
22. The method of any one of claims 1-21, wherein:
the PPAR δ agonist compound is a phenoxyacetic acid compound, a phenoxypropionic acid compound, a phenoxybutyric acid compound, a phenoxyvaleric acid compound, a phenoxyhexanoic acid compound, a phenoxyoctanoic acid compound, a phenoxynonanoic acid compound, or a phenoxydecanoic acid compound.
23. The method of any one of claims 1-21, wherein:
the PPAR δ agonist compound is a phenoxyacetic acid compound or a phenoxyhexanoic acid compound.
24. The method of claim 21, wherein:
the PPAR δ agonist compound is an allyloxyphenoxyacetic acid compound.
25. The method of any one of claims 1-19, wherein the PPAR δ agonist compound is:
(E) -4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid;
(Z) - [ 2-methyl-4- [3- (4-methylphenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -phenoxy ] acetic acid;
(E) - [ 2-methyl-4- [3- [4- [3- (pyrazol-1-yl) prop-1-ynyl ] phenyl ] -3- (4-trifluoromethylphenyl) -allyloxy ] phenoxy ] acetic acid;
(E) - [ 2-methyl-4- [3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] -3- (4-trifluoromethylphenyl) allyloxy ] -phenoxy ] acetic acid;
(E) -4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid;
(E) - [4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methylphenyl ] -propionic acid;
{4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -benzylsulfanyl ] -2-methyl-phenoxy } -acetic acid;
{4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -phenylthio ] -2-methyl-phenoxy } -acetic acid; or
{4- [3, 3-bis- (4-bromo-phenyl) -allyloxy ] -2-methyl-phenoxy } -acetic acid;
or a pharmaceutically acceptable salt thereof.
26. The method of any one of claims 1-20, wherein the PPAR δ agonist compound is:
(E) -4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid;
(Z) - [ 2-methyl-4- [3- (4-methylphenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -phenoxy ] acetic acid;
(E) - [ 2-methyl-4- [3- [4- [3- (pyrazol-1-yl) prop-1-ynyl ] phenyl ] -3- (4-trifluoromethylphenyl) -allyloxy ] phenoxy ] acetic acid;
(E) - [ 2-methyl-4- [3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] -3- (4-trifluoromethylphenyl) allyloxy ] -phenoxy ] acetic acid;
(E) -4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid;
(E) - [4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methylphenyl ] -propionic acid;
{4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -benzylsulfanyl ] -2-methyl-phenoxy } -acetic acid;
{4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -phenylthio ] -2-methyl-phenoxy } -acetic acid;
{4- [3, 3-bis- (4-bromo-phenyl) -allyloxy ] -2-methyl-phenoxy } -acetic acid;
(R) -3-methyl-6- (2- ((5-methyl-2- (4- (trifluoromethyl) phenyl) -1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid;
(R) -3-methyl-6- (2- ((5-methyl-2- (6- (trifluoromethyl) pyridin-3-yl) -1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid;
2- {4- [ ({2- [ 2-fluoro-4- (trifluoromethyl) phenyl ] -4-methyl-1, 3-thiazol-5-yl } methyl) thio ] -2-methylphenoxy } -2-methylpropionic acid (soglitazar; GW 677954);
2- [ 2-methyl-4- [ [ 3-methyl-4- [ [4- (trifluoromethyl) phenyl ] methoxy ] phenyl ] thio ] phenoxy ] -acetic acid;
2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] methyl ] thio ] phenoxy ] -acetic acid (GW-501516);
[4- [ [ [2- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -4-methyl-5-thiazolyl ] methyl ] thio ] -2-methylphenoxy ] acetic acid (GW0742, also known as GW 610742);
2- [2, 6-dimethyl-4- [3- [4- (methylthio) phenyl ] -3-oxo-1 (E) -propenyl ] phenoxy ] -2-methylpropanoic acid (elafinidor; GFT-505);
{ 2-methyl-4- [ 5-methyl-2- (4-trifluoromethyl-phenyl) -2H- [1,2,3] triazol-4-ylmethylsulfanyl ] -phenoxy } -acetic acid;
[4- ({ (2R) -2-ethoxy-3- [4- (trifluoromethyl) phenoxy ] propyl } thio) -2-methylphenoxy ] acetic acid (seladelpar; MBX-8025);
(S) -4- [ cis-2, 6-dimethyl-4- (4-trifluoromethoxy-phenyl) piperazine-1-sulfonyl ] -indan-2-carboxylic acid or its tosylate salt (KD-3010);
(2s) -2- { 4-butoxy-3- [ ({ [ 2-fluoro-4- (trifluoromethyl) phenyl ] carbonyl } amino) methyl ] benzyl } butanoic acid (TIPP-204);
[4- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy ] phenoxy ] acetic acid (L-165,0411);
2- (4- {2- [ (4-chlorobenzoyl) amino ] ethyl } phenoxy) -2-methylpropanoic acid (bezafibrate);
2- (2-methyl-4- (((2- (4- (trifluoromethyl) phenyl) -2H-1,2, 3-triazol-4-yl) methyl) thio) phenoxy) acetic acid; or
(R) -2- (4- ((2-ethoxy-3- (4- (trifluoromethyl) phenoxy) propyl) thio) phenoxy) acetic acid;
or a pharmaceutically acceptable salt thereof.
27. The method of any one of claims 1-20, wherein:
the PPAR δ agonist compound is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof.
28. The method of any one of claims 1-20, wherein:
the PPAR δ agonist compound is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof, and is administered to the mammal in a dose of from about 10mg to about 500 mg.
29. The method of any one of claims 1-20, wherein:
the PPAR δ agonist compound is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof, and is administered to the mammal in a dose of from about 50mg to about 200 mg.
30. The method of any one of claims 1-20, wherein:
the PPAR δ agonist compound is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof, and is administered to the mammal in a dose of from about 75mg to about 125 mg.
31. The method of any one of claims 1-20, wherein:
the PPAR δ agonist compound is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof, and is administered to the mammal at a dose of about 50 mg.
32. The method of any one of claims 1-20, wherein:
the PPAR δ agonist compound is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof, and is administered to the mammal at a dose of about 100 mg.
33. The method of any one of claims 1-32, wherein:
the PPAR δ agonist compound is administered systemically to the mammal.
34. The method of claim 33, wherein:
the PPAR δ agonist compound is administered to the mammal in the form of an oral solution, oral suspension, powder, pill, tablet or capsule.
35. The method of any one of claims 1-34, wherein:
the PPAR δ agonist compound is administered to the mammal daily.
36. The method of any one of claims 1-34, wherein:
the PPAR δ agonist compound is administered to the mammal once daily.
37. The method of any of claims 1-35, further comprising:
administering at least one additional therapeutic agent to the mammal.
38. The method of claim 37, wherein:
the at least one additional therapeutic agent is panthenol, ubiquinone, niacin, riboflavin, creatine, L-carnitine, acetyl-L-carnitine, biotin, thiamine, pantothenic acid, pyridoxine, alpha-lipoic acid, N-heptanoic acid, CoQ10, vitamin E, vitamin C, methylcobalamin, folinic acid, N-acetyl-L-cysteine (NAC), zinc, folinic acid/leucovorin calcium, resveratrol acipimox, elamipramitide, cysteamine, succinate, an NAD agonist, vaquitinone (EPI-743), omaloxolone (RTA-408), niacin, nicotinamide, elamipramitide, KL133, KH176, or a combination thereof.
39. The method of claim 37, wherein:
the at least one additional therapeutic agent is an odd chain fatty acid, an odd chain fatty ketone, L-carnitine, or a combination thereof.
40. The method of claim 37, wherein:
the at least one additional therapeutic agent is triheptanoin, n-heptanoic acid, triglyceride, or salts thereof, or combinations thereof.
41. The method of any one of claims 1-40, wherein the mammal is a human.
42. A method for treating a primary mitochondrial myopathy in a mammal, comprising administering a PPAR agonist compound to the mammal having the primary mitochondrial myopathy, wherein the PPAR agonist compound is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid, or a pharmaceutically acceptable salt thereof.
43. The method of claim 42, wherein:
treating the primary mitochondrial myopathy comprises increasing oxidative phosphorylation (OXPHOS) in the mammal, improving exercise tolerance, improving muscle histology, improving mitochondrial DNA copy number, improving the level of heterogeneity, improving mitochondrial mass, reducing pain, reducing fatigue, improving cognition, improving overall health, increasing survival, or a combination thereof.
44. The method of claim 42 or claim 43, wherein:
the peroxisome proliferator-activated receptor delta (PPAR δ) agonist compound is administered to a mammal in an amount sufficient to increase OXPHOS capacity in the mammal, up-regulate gene expression of any of the enzymes or proteins involved in OXPHOS, or a combination thereof.
45. The method of any one of claim 43 or claim 44, wherein:
the peroxisome proliferator-activated receptor delta (PPAR δ) agonist compound is administered to the mammal in an amount sufficient to increase Fatty Acid Oxidation (FAO) capacity in the mammal, up-regulate gene expression of any of the enzymes or proteins involved in FAO, or a combination thereof.
46. The method of any one of claims 42-45, wherein the mammal having primary mitochondrial myopathy has:
-at least one mutation or deletion in at least one mitochondrial dna (mtdna) gene;
-at least one mitochondrial dna (mtdna) defect;
-at least one mutation or deletion in at least one nuclear dna (ndna) gene involved in mitochondrial function; or
-combinations thereof.
47. The method of claim 46, wherein:
the at least one mutation in the at least one mitochondrial DNA (mtDNA) gene comprises a mutation selected from the group consisting of m.3243A > G, m.8344A > G, m.8993T > G, m.13513G > A, m.11778G > A, m.14484T > C, and a combination thereof;
or the at least one mutation in the at least one mitochondrial DNA (mtDNA) gene comprises a mutation selected from the group consisting of an 8284bp deletion, a 6277bp deletion, a 4977bp deletion, and combinations thereof;
the at least one mutation or deletion in at least one nuclear DNA (nDNA) gene involved in mitochondrial function includes at least one mutation or deletion in the nDNA gene encoding complex I (NADH: ubiquinone oxidoreductase), complex II (succinate dehydrogenase), complex III (CoQ-cytochrome c reductase), complex IV (cytochrome c oxidase), complex V (ATP synthase), aminoacyl-tRNA synthetase, release factor, elongation factor, mitochondrial ribosomal protein, thiamine, and phosphate, or a combination thereof.
48. The method of claim 47, wherein:
the gene encoding the compound I comprises NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NDUFA1, NDUFA2, NDUFA9, NDUFA10, NDUFA11, NDUFA12, NDUFA13, NDUFAF2, NDUFAF6 or NDUFB 11;
the gene encoding complex II comprises SDHA, SDHB, SDHC, SDHD or SDHAF 1;
the gene encoding complex III comprises UQCRB, BCS1L, UQCRQ, UQCRC2, CYC1, TTC19, LYRM7, UQCC2, or UQCC 3;
the gene encoding compound IV comprises COA5, SURF1, COX10, COX14, COX15, COX20, COX6B1, FASTKD2, SCO1, SCO2, LRPRC, TACO1 or PET 100;
the gene encoding complex V comprises ATPAF2, TMEM70, ATP5E, or ATP5a 1;
the genes encoding aminoacyl-tRNA synthetases include AARS2, DARS2, EARS2, RARS2, YARS2, FARS2, HARS2, LARS2, VARS2, TARS2, IARS2, CARS2, PARS2, NARS2, KARS, GARS, SARS2, or MARS 2;
the gene encoding a release factor includes C12orf 65;
the gene encoding an elongation factor comprises TUFM, TSFM or GFM 1;
the genes encoding mitochondrial ribosomal proteins include MRPS16, MRPS22, MRPL3, MRP12, or MRPL 44; and is
The genes encoding the solute carriers of thiamine and phosphate include SLC19A3, SLC25A3, or SLC25A 19.
49. The method of claim 46, wherein:
the at least one mutation or deletion in at least one nuclear dna (nDNA) gene involved in mitochondrial function includes at least one mutation or deletion in the nDNA gene involved in phospholipid metabolism, toxic compound metabolism, disulfide-relay systems, ferritin assembly, tRNA modification, mRNA processing, mitochondrial fusion or fission, deoxynucleotide triphosphate synthesis, protein quality control and degradation, ATP and ADP transport, or a combination thereof.
50. The method of claim 49, wherein:
the genes involved in phospholipid metabolism include AGK, SERAC1 or TAZ;
the genes involved in toxic compound metabolism include HIBCH, ECHS1, ETHE1 or MPV 17;
the genes involved in the disulfide relay system include GFER;
the genes involved in ferrothionein assembly include ISCU, BOLA3, NFU1, or IBA 57;
the genes involved in tRNA modification include MTO1, GTP3BP, TRMU, PUS1, MTFMT, TRIT1, TRNT1, or TRMT 5;
the genes involved in mRNA processing include LRPRC, TACO1, ELAC2, PNPT1, HSD17B10, MTPAP or PTCD 1;
the genes involved in mitochondrial fusion and fission comprise OPA1 or MFN 2;
the genes involved in deoxynucleotide triphosphate synthesis include DGUOK, TK2, TYMP, MGME1, SUCLG1, SUCLA2, RNASEH1, C10orf2, POLG2, DNA2, or RRM 2B;
the genes involved in protein quality control and degradation include FBXL4, AFG3L2, or SPG 7; and is
The genes involved in ATP and ADP transport include ANT 1.
51. The method of any one of claims 42-50, wherein:
the mammal has been diagnosed with Kearns-Sayre syndrome (KSS), Leigh syndrome, Maternally Inherited Leigh Syndrome (MILS), mitochondrial DNA depletion syndrome (MDS), mitochondrial encephalomyopathy, lactic acidosis and stroke-like attacks (MELAS), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with fragmented red fibers (MERRF), Neurological Ataxia and Retinitis Pigmentosa (NARP), Pearson syndrome, or progressive extraocular Paralysis (PEO).
52. The method of any one of claims 42-51, wherein:
the mammal having the primary mitochondrial myopathy further comprises a secondary mitochondrial myopathy.
53. The method of claim 52, wherein:
the secondary mitochondrial myopathy comprises a secondary defect in OXPHOS function caused by the primary FAO defect, or the secondary mitochondrial myopathy is caused by a primary OXPHOS deficiency leading to a secondary FAO disease.
54. The method of any one of claims 42-53, wherein the PPAR δ agonist compound increases the expression or activity of a gene or protein involved in mitochondrial biogenesis.
55. The method of claim 54, wherein the protein is peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1 a).
56. The method of any one of claims 42-55, wherein the PPAR δ agonist compound increases the expression or activity of a gene involved in oxidative phosphorylation or a protein thereof.
57. The method of any one of claims 42-56, wherein the PPAR δ agonist compound increases the percentage of non-mutated mitochondrial DNA (mtDNA) relative to the proportion of mutated mtDNA.
58. The method of any one of claims 42-57, wherein:
(E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof is administered to the mammal in a dose of about 10mg to about 500 mg.
59. The method of any one of claims 42-57, wherein:
(E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof is administered to the mammal in a dose of about 50mg to about 200 mg.
60. The method of any one of claims 42-57, wherein:
(E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof is administered to the mammal at a dose of about 75mg to about 125 mg.
61. The method of any one of claims 42-57, wherein:
(E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof is administered to the mammal in a dose of about 50 mg.
62. The method of any one of claims 42-57, wherein:
(E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof is administered to the mammal at a dose of about 100 mg.
63. The method of any one of claims 42-62, wherein:
(E) -4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid, or a pharmaceutically acceptable salt thereof, is administered systemically to the mammal in the form of an oral solution, oral suspension, powder, pill, tablet or capsule.
64. The method of any one of claims 42-63, wherein:
the PPAR δ agonist compound is administered to the mammal daily.
65. The method of any one of claims 42-63, wherein:
the PPAR δ agonist compound is administered to the mammal once daily.
66. The method of any of claims 42-65, further comprising:
administering at least one additional therapeutic agent to the mammal.
67. The method of claim 66, wherein:
the at least one additional therapeutic agent is panthenol, ubiquinone, niacin, riboflavin, creatine, L-carnitine, acetyl-L-carnitine, biotin, thiamine, pantothenic acid, pyridoxine, alpha-lipoic acid, N-heptanoic acid, CoQ10, vitamin E, vitamin C, methylcobalamin, folinic acid, N-acetyl-L-cysteine (NAC), zinc, folinic acid/leucovorin calcium, resveratrol, acipimox, elamipramitide, cysteamine, succinate, a NAD agonist, vaquitinone (EPI-743)), omaloxolone (RTA-408), niacin, nicotinamide, elamipramide, KL133, KH176, or a combination thereof.
68. The method of claim 66, wherein:
the at least one additional therapeutic agent is an odd chain fatty acid, an odd chain fatty ketone, L-carnitine, or a combination thereof.
69. The method of claim 66, wherein:
the at least one additional therapeutic agent is triheptanoin, n-heptanoic acid, triglyceride, or a salt thereof, or a combination thereof.
70. The method of any one of claims 42-69, wherein the mammal is a human.
71. A method for treating a primary mitochondrial myopathy in a human comprising administering a PPAR δ agonist compound to the mammal having the primary mitochondrial myopathy, wherein after treatment the mammal has an improvement in one or more of pain, cognition, physical endurance, muscle strength, wellness, or increased survival.
72. The method of claim 71, wherein the improvement is physical endurance.
73. The method of claim 72, wherein the improvement is physical endurance, as evidenced by one or more improvements in walking endurance or sit-stand testing.
74. The method of claim 71, wherein the improvement is muscle strength.
75. The method of claim 74, wherein the muscle strength is measured by grip strength or leg strength.
76. The method of claim 71, wherein the improvement is increased survival in a human.
77. The method of any one of claims 71-76, wherein the PPAR δ agonist compound is:
(E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof and is administered to the mammal in a dose of from about 10mg to about 500 mg.
78. The method of claim 77, wherein:
(E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof is administered to the mammal in a dose of about 50mg to about 200 mg.
79. The method of any one of claims 77, wherein:
(E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof is administered to the mammal at a dose of about 75mg to about 125 mg.
80. The method of any one of claims 77, wherein:
(E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof is administered to the mammal in a dose of about 50 mg.
81. The method of claim 77, wherein:
(E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof is administered to the mammal at a dose of about 100 mg.
82. The method of any one of claims 77-81, wherein:
(E) -4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid, or a pharmaceutically acceptable salt thereof, is administered systemically to the mammal in the form of an oral solution, oral suspension, powder, pill, tablet or capsule.
83. The method of claims 71-82, wherein the PPAR δ agonist compound is administered to the mammal daily.
84. The method of claim 83, wherein the PPAR δ agonist compound is administered to the mammal once per day.
85. The method of any one of claims 71-84, further comprising administering at least one additional therapeutic agent.
86. The method of claim 85, wherein the at least one additional therapeutic agent is panthenol, ubiquinone, niacin, riboflavin, creatine, L-carnitine, acetyl-L-carnitine, biotin, thiamine, pantothenic acid, pyridoxine, alpha-lipoic acid, N-heptanoic acid, CoQ10, vitamin E, vitamin C, methylcobalamin, folinic acid, N-acetyl-L-cysteine (NAC), zinc, calcium folinate/leucovorin, resveratrol, acipimox, elamipramitide, cysteamine, succinate, an NAD agonist, vatiquine (EPI-743)), omaloxolone (RTA-408), niacin, nicotinamide, elamipramitide, KL133, KH176, or a combination thereof.
87. The method of claim 85, wherein the at least one additional therapeutic agent is an odd chain fatty acid, an odd chain fatty ketone, L-carnitine, or a combination thereof.
88. The method of claim 85, wherein the at least one additional therapeutic agent is triheptanoin, n-heptanoic acid, triglycerides, or salts thereof, or combinations thereof.
Technical Field
Described herein are methods of treating or preventing mitochondrial myopathy using peroxisome proliferator-activated receptor delta (PPAR δ) agonists.
Background
Healthy mitochondria are critical to normal cellular activity. Mitochondrial dysfunction drives the pathogenesis of a variety of medical conditions including acute conditions and chronic diseases. Different aspects of mitochondrial function, e.g., bioenergetics, kinetics and cell signaling, have been well described, and impairment of these activities may contribute to the pathogenesis of the disease. Impaired mitochondrial function results in a series of conditions known as primary mitochondrial myopathy. Primary Mitochondrial Myopathy (PMM) is a genetically defined disorder that results in a deficiency in oxidative phosphorylation, primarily but not exclusively affecting skeletal muscle. PAR δ is a member of the nuclear regulatory superfamily of ligand-activated transcriptional regulators and is expressed systemically. PPAR δ agonists induce genes associated with fatty acid oxidation and mitochondrial biogenesis. PPAR δ also has anti-inflammatory properties.
Disclosure of Invention
In one aspect, described herein is a method for treating a Primary Mitochondrial Myopathy (PMM) in a mammal comprising administering a peroxisome proliferator activated receptor delta (PPAR δ) agonist compound to a mammal having a primary mitochondrial myopathy.
In another aspect, described herein is a method of modulating PPAR δ in a mammal having a primary mitochondrial myopathy, comprising administering a PPAR δ agonist compound to a mammal having a primary mitochondrial myopathy.
In some embodiments, treating the primary mitochondrial myopathy comprises increasing oxidative phosphorylation (OXPHOS) in the mammal, improving exercise tolerance, alleviating pain, reducing fatigue, improving cognition, improving overall health, increasing survival, or a combination thereof in the mammal. In some embodiments, the PPAR δ agonist compound is administered to the mammal in an amount sufficient to increase OXPHOS ability in the mammal, up-regulate gene expression of any one of an enzyme or protein involved in OXPHOS, or a combination thereof.
In some embodiments, the PPAR δ agonist compound is administered to the mammal in an amount sufficient to improve oxidative phosphorylation ability in the mammal, up-regulate gene expression of any one of an enzyme or protein involved in oxidative phosphorylation, or a combination thereof.
In yet another aspect, described herein is a method for increasing Fatty Acid Oxidation (FAO) in a mammal having a primary mitochondrial myopathy comprising administering a PPAR δ agonist compound to a mammal having a primary mitochondrial myopathy. In some embodiments, the PPAR δ agonist compound is administered to the mammal in an amount sufficient to improve FAO capability in the mammal, up-regulate gene expression of any one of an enzyme or protein involved in FAO, or a combination thereof.
In some embodiments, the mammal having a primary mitochondrial myopathy has: at least one mutation or deletion in at least one mitochondrial DNA (mtDNA) gene; at least one mitochondrial dna (mtdna) defect; at least one mutation or deletion in at least one nuclear dna (ndna) gene involved in mitochondrial function; or a combination thereof.
In some embodiments, the at least one mutation in the at least one mitochondrial dna (mtdna) gene comprises a mutation selected from the group consisting of m.3243a > G, m.8344a > G, m.8993t > G, m.13513g > a, m.11778g > a, m.14484t > C, and combinations thereof. In some embodiments, the at least one mutation in the at least one mitochondrial dna (mtdna) gene comprises the mutation m.3243a > G.
In some embodiments, the at least one mutation in the at least one mitochondrial dna (mtdna) gene comprises a mutation selected from the group consisting of an 8284bp deletion, a 6277bp deletion, a 4977bp deletion, and combinations thereof.
In some embodiments, the at least one mutation or deletion in the at least one nuclear DNA (nDNA) gene involved in mitochondrial function comprises at least one mutation or deletion in the nDNA gene encoding a solute carrier for Complex I (NADH: ubiquinone oxidoreductase), Complex II (succinate dehydrogenase), Complex III (CoQ-cytochrome c reductase), Complex IV (cytochrome c oxidase), Complex V (ATP synthase), aminoacyl tRNA synthetase, Release factor, elongation factor, mitochondrial ribosomal protein, thiamine, and phosphate. In some embodiments, the gene encoding complex I comprises ndifs 1, ndifs 2, ndifs 3, ndifs 4, ndifs 6, ndifs 7, ndifs 8, ndifv 1, ndifv 2, ndifa 1, ndifa 2, ndifa 9, ndifa 10, ndifa 11, ndifa 12, ndifa 13, ndifa 2, ndifa 6, or ndifb 11. In some embodiments, the gene encoding complex II comprises SDHA, SDHB, SDHC, SDHD, or SDHAF 1. In some embodiments, the gene encoding complex III comprises UQCRB, BCS1L, UQCRQ, UQCRC2, CYC1, TTC19, LYRM7, UQCC2, or UQCC 3. In some embodiments, the gene encoding complex IV comprises COA5, SURF1, COX10, COX14, COX15, COX20, COX6B1, FASTKD2, SCO1, SCO2, LRPPRC, TACO1, or PET 100. In some embodiments, the gene encoding complex V comprises ATPAF2, TMEM70, ATP5E, or ATP5a 1. In some embodiments, the gene encoding the aminoacyl-tRNA synthetase comprises AARS2, DARS2, EARS2, RARS2, YARS2, FARS2, HARS2, LARS2, VARS2, TARS2, IARS2, CARS2, PARS2, NARS2, KARS, GARS, SARS2, or MARS 2. In some embodiments, the gene encoding a release factor comprises C12orf 65. In some embodiments, the gene encoding an elongation factor comprises TUFM, TSFM, or GFM 1. In some embodiments, the gene encoding a mitochondrial ribosomal protein comprises MRPS16, MRPS22, MRPL3, MRP12, or MRPL 44. In some embodiments, the gene encoding a solute carrier for thiamine and phosphate comprises SLC19A3, SLC25A3, or SLC25a 19.
In some embodiments, the at least one mutation or deletion in at least one nuclear dna (nDNA) gene involved in mitochondrial function comprises at least one mutation or deletion in the nDNA gene involved in phospholipid metabolism, toxic compound metabolism, disulfide relay systems, iron sulfur protein assembly, tRNA modification, mRNA processing, mitochondrial fusion or fission, deoxynucleotide triphosphate synthesis, protein quality control and degradation, ATP and ADP transport, or a combination thereof. In some embodiments, the gene involved in phospholipid metabolism comprises AGK, SERAC1, or TAZ. In some embodiments, the genes involved in toxic compound metabolism include HIBCH, ECHS1, ete 1, or MPV 17. In some embodiments, the gene involved in the disulfide relay system comprises GFER. In some embodiments, the genes involved in ferrithioprotein assembly include ISCU, BOLA3, NFU1, or IBA 57. In some embodiments, the gene involved in tRNA modification comprises MTO1, GTP3BP, TRMU, PUS1, MTFMT, TRIT1, TRNT1, or TRMT 5. In some embodiments, the genes involved in mRNA processing include LRPPRC, TACO1, ELAC2, PNPT1, HSD17B10, MTPAP, or PTCD 1. In some embodiments, the genes involved in mitochondrial fusion and fission include OPA1 or MFN 2. In some embodiments, the genes involved in deoxynucleotide triphosphate synthesis include DGUOK, TK2, TYMP, MGME1, SUCLG1, SUCLA2, RNASEH1, C10orf2, POLG2, DNA2, or RRM 2B. In some embodiments, genes involved in protein quality control and degradation include FBXL4, AFG3L2, or SPG 7. In some embodiments, the genes involved in ATP and ADP transport include ANT 1.
In some embodiments, the mammal has been diagnosed with Kearns-Sayre syndrome (KSS), Leigh syndrome, Maternally Inherited Leigh Syndrome (MILS), mitochondrial DNA depletion syndrome (MDS), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like attacks (MELAS), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with broken red fibers (MERRF), neuroataxia and retinitis pigmentosa (NARP), Pearson syndrome, or progressive extraocular muscular Palsy (PEO).
In some embodiments, the mammal having the primary mitochondrial myopathy further comprises a secondary mitochondrial myopathy. In some embodiments, the secondary mitochondrial myopathy is a hereditary secondary mitochondrial myopathy. In some embodiments, the secondary mitochondrial myopathy is an acquired secondary mitochondrial myopathy. In some embodiments, the secondary mitochondrial myopathy involves a secondary defect in OXPHOS function due to a primary FAO defect, or the secondary mitochondrial myopathy results from a primary OXPHOS deficiency leading to a secondary FAO disease.
In some embodiments, the PPAR δ agonist activates PPAR δ. In some embodiments, the PPAR δ agonist increases the activity of PPAR δ. In some embodiments, the PPAR δ agonist increases mitochondrial biogenesis. In some embodiments, the PPAR δ agonist increases the expression or activity of a gene or protein involved in mitochondrial biogenesis. In some embodiments, the protein is peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1 alpha). In some embodiments, the PPAR δ agonist increases the expression or activity of a gene involved in oxidative phosphorylation or a protein thereof.
In some embodiments, the PPAR δ agonist increases the percentage of unmutated mitochondrial dna (mtDNA) relative to the ratio of mutated mtDNA. In some embodiments, the percentage of unmutated mtDNA increases by at least 10% following treatment with a PPAR δ agonist compound. In some embodiments, the percentage of unmutated mtDNA increases by about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, or about 10% to about 90% upon treatment with a PPAR δ agonist compound.
In some embodiments, the PPAR δ agonist compound binds to and activates cellular PPAR δ and does not substantially activate cellular peroxisome proliferator-activated receptor- α (PPAR α) and cellular peroxisome proliferator-activated receptor- γ (PPAR γ).
In some embodiments, the PPAR δ agonist compound is a phenoxyalkylcarboxylic acid compound. In some embodiments, the PPAR δ agonist compound is a phenoxyacetic acid compound, a phenoxypropionic acid compound, a phenoxybutyric acid compound, a phenoxyvaleric acid compound, a phenoxyhexanoic acid compound, a phenoxyoctanoic acid compound, a phenoxynonanoic acid compound, or a phenoxydecanoic acid compound. In some embodiments, the PPAR δ agonist compound is a phenoxyacetic acid compound or a phenoxyhexanoic acid compound. In some embodiments, the PPAR δ agonist compound is an allyloxyphenoxyacetic acid compound.
In some embodiments, the PPAR δ agonist is a compound selected from the group consisting of: (Z) - [ 2-methyl-4- [3- (4-methylphenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -phenoxy ] acetic acid; (E) - [ 2-methyl-4- [3- [4- [3- (pyrazol-1-yl) prop-1-ynyl ] phenyl ] -3- (4-trifluoromethylphenyl) -allyloxy ] phenoxy ] acetic acid; (E) -4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid; (E) - [ 2-methyl-4- [3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] -3- (4-trifluoromethylphenyl) allyloxy ] -phenoxy ] acetic acid; (E) -4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid; (E) - [4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methylphenyl ] -propionic acid; {4- [3, 3-bis- (4-bromo-phenyl) -allyloxy ] -2-methyl-phenoxy } -acetic acid; or a pharmaceutically acceptable salt thereof.
In some embodiments, the PPAR δ agonist compound is a compound selected from the group consisting of: (Z) - [ 2-methyl-4- [3- (4-methylphenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -phenoxy ] acetic acid; (E) - [ 2-methyl-4- [3- [4- [3- (pyrazol-1-yl) prop-1-ynyl ] phenyl ] -3- (4-trifluoromethylphenyl) -allyloxy ] phenoxy ] acetic acid; (E) -4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid; (E) - [ 2-methyl-4- [3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] -3- (4-trifluoromethylphenyl) allyloxy ] -phenoxy ] acetic acid; (E) -4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid; (E) - [4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methylphenyl ] -propionic acid; {4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -benzylsulfanyl ] -2-methyl-phenoxy } -acetic acid; {4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -phenylthio ] -2-methyl-phenoxy } -acetic acid; {4- [3, 3-bis- (4-bromo-phenyl) -allyloxy ] -2-methyl-phenoxy } -acetic acid; 2- [ 2-methyl-4- [ [ 3-methyl-4- [ [4- (trifluoromethyl) phenyl ] methoxy ] phenyl ] thio ] phenoxy ] -acetic acid; (S) -4- [ cis-2, 6-dimethyl-4- (4-trifluoromethoxy-phenyl) piperazine-1-sulfonyl ] -indan-2-carboxylic acid or its tosylate salt (KD-3010); (2s) -2- { 4-butoxy-3- [ ({ [ 2-fluoro-4- (trifluoromethyl) phenyl ] carbonyl } amino) methyl ] benzyl } butanoic acid (TIPP-204); 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] methyl ] thio ] phenoxy ] -acetic acid (GW-501516); 2- [2,6 dimethyl-4- [3- [4- (methylthio) phenyl ] -3-oxo-1 (E) -propenyl ] phenoxy ] -2-methylpropanoic acid (GFT-505); { 2-methyl-4- [ 5-methyl-2- (4-trifluoromethyl-phenyl) -2H- [1,2,3] triazol-4-ylmethylsulfanyl ] -phenoxy } -acetic acid; (R) -3-methyl-6- (2- ((5-methyl-2- (4- (trifluoromethyl) phenyl) -1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid; (R) -3-methyl-6- (2- ((5-methyl-2- (6- (trifluoromethyl) pyridin-3-yl) -1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid; 2- (2-methyl-4- (((2- (4- (trifluoromethyl) phenyl) -2H-1,2, 3-triazol-4-yl) methyl) thio) phenoxy) acetic acid; and (R) -2- (4- ((2-ethoxy-3- (4- (trifluoromethyl) phenoxy) propyl) thio) phenoxy) acetic acid; or a pharmaceutically acceptable salt thereof.
In some embodiments, the PPAR δ agonist compound is a compound selected from the group consisting of: (Z) - [ 2-methyl-4- [3- (4-methylphenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -phenoxy ] acetic acid; (E) - [ 2-methyl-4- [3- [4- [3- (pyrazol-1-yl) prop-1-ynyl ] phenyl ] -3- (4-trifluoromethylphenyl) -allyloxy ] phenoxy ] acetic acid; (E) -4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid; (E) - [ 2-methyl-4- [3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] -3- (4-trifluoromethylphenyl) allyloxy ] -phenoxy ] acetic acid; (E) -4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid; (E) - [4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methylphenyl ] -propionic acid; {4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -benzylsulfanyl ] -2-methyl-phenoxy } -acetic acid; {4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -phenylthio ] -2-methyl-phenoxy } -acetic acid; and {4- [3, 3-bis- (4-bromo-phenyl) -allyloxy ] -2-methyl-phenoxy } -acetic acid; or a pharmaceutically acceptable salt thereof.
In some embodiments, the PPAR δ agonist is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid (compound I) or a pharmaceutically acceptable salt thereof. In some embodiments, the PPAR δ agonist is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof, and is administered to the mammal at a dose of about 10mg to about 500 mg. In some embodiments, the PPAR δ agonist is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof, and is administered to the mammal at a dose of about 50mg to about 200 mg. In some embodiments, the PPAR δ agonist is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid (compound I), or a pharmaceutically acceptable salt thereof, and is administered to the mammal in a dose of from about 75mg to about 125 mg. In some embodiments, the PPAR δ agonist compound is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof, and is administered to the mammal at a dose of about 50 mg. In some embodiments, the PPAR δ agonist compound is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof, and is administered to the mammal at a dose of about 100 mg.
In another aspect, provided herein is a method for treating a primary mitochondrial myopathy in a mammal comprising administering a PPAR agonist compound to a mammal having a primary mitochondrial myopathy, wherein the PPAR agonist compound is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid, or a pharmaceutically acceptable salt thereof.
In some embodiments, treating the primary mitochondrial myopathy comprises increasing oxidative phosphorylation (OXPHOS) in the mammal, improving exercise tolerance, improving muscle histology, improving mitochondrial DNA copy number, improving the level of heterogeneity, improving mitochondrial mass, reducing pain, reducing fatigue, improving cognition, improving overall health, increasing survival, or a combination thereof.
In some embodiments, the peroxisome proliferator-activated receptor delta (PPAR δ) agonist compound is administered to the mammal in an amount sufficient to increase OXPHOS capacity in the mammal, up-regulate gene expression of any one of an enzyme or protein involved in OXPHOS, or a combination thereof. In some embodiments, the peroxisome proliferator-activated receptor delta (PPAR δ) agonist compound is administered to the mammal in an amount sufficient to increase Fatty Acid Oxidation (FAO) capacity in the mammal, up-regulate gene expression of any of an enzyme or protein involved in the FAO, or a combination thereof.
In another aspect, provided herein is a method for treating a primary mitochondrial myopathy in a human comprising administering a PPAR δ agonist compound to a mammal having the primary mitochondrial myopathy, wherein after treatment the mammal has an improvement in one or more of pain, cognition, physical endurance, muscle strength, well-being or increased survival.
In some embodiments, the improvement is physical endurance. In some embodiments, the improvement is physical endurance, as evidenced by one or more improvements in walking endurance or sit-stand testing. In some embodiments, the improvement is muscle strength. In some embodiments, muscle strength is measured by grip strength or leg strength. In some embodiments, the improvement is increasing survival in a human.
In some embodiments, the PPAR δ agonist compound is: (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof and is administered to the mammal in a dose of about 10mg to about 500 mg. In some embodiments, (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof is administered to the mammal at a dose of about 50mg to about 200 mg. In some embodiments, (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof is administered to the mammal at a dose of about 75mg to about 125 mg. In some embodiments, (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof is administered to the mammal at a dose of about 50 mg. In some embodiments, (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof is administered to the mammal at a dose of about 100 mg. In some embodiments, (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof is administered systemically to the mammal in the form of an oral solution, oral suspension, powder, pill, tablet or capsule. In some embodiments, the PPAR agonist compound is administered to the mammal daily. In some embodiments, the PPAR δ agonist compound is administered to the mammal once daily.
In some embodiments, the PPAR δ agonist is administered to the mammal systemically. In some embodiments, the PPAR δ agonist is administered to the mammal orally, by injection, or intravenously. In some embodiments, the PPAR δ agonist is administered to the mammal in the form of an oral solution, oral suspension, powder, pill, tablet, or capsule.
In one aspect, described herein is a pharmaceutical composition comprising a PPAR δ agonist and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ocular administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, or oral administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule.
In any of the preceding aspects is a further embodiment, wherein the effective amount of the PPAR δ agonist (e.g., compound I or a pharmaceutically acceptable salt thereof) is: (a) systemically administering to the mammal; and/or (b) orally administered to the mammal; and/or (c) administered intravenously to the mammal; and/or (d) is administered to the mammal by injection; and/or (e) non-systemically or topically administered to the mammal.
In any of the preceding aspects is a further embodiment, which comprises a single administration of the effective amount of the PPAR δ agonist (e.g., compound I or a pharmaceutically acceptable salt thereof), including a further embodiment, wherein the PPAR δ agonist (e.g., compound I or a pharmaceutically acceptable salt thereof) is administered to the mammal once daily or multiple times over a time span of one day. In some embodiments, the PPAR δ agonist (e.g., compound I or a pharmaceutically acceptable salt thereof) is administered in a continuous dosing schedule. In some embodiments, the PPAR δ agonist is administered on a continuous daily dosing schedule.
In any of the preceding aspects or embodiments relating to the treatment of a disease or condition is a further embodiment comprising administering at least one additional agent in addition to the PPAR δ agonist (e.g., compound I or a pharmaceutically acceptable salt thereof). In some embodiments, the at least one additional therapeutic agent is panthenol, ubiquinone, niacin, riboflavin, creatine, L-carnitine, acetyl-L-carnitine, biotin, thiamine, pantothenic acid, pyridoxine, alpha-lipoic acid, N-heptanoic acid, CoQ10, vitamin E, vitamin C, methylcobalamin, folinic acid, N-acetyl-L-cysteine (NAC), zinc, calcium folinic acid/leucovorin, resveratrol, acipimox, elamipramitide, cysteamine, succinate, an NAD agonist, vatiquinone (EPI-743)), omaloxolone (RTA-408), niacin, nicotinamide, elamipramide, KL133, KH176, or a combination thereof. In some embodiments, the at least one additional therapeutic agent is an odd chain fatty acid, an odd chain fatty ketone, L-carnitine, or a combination thereof. In some embodiments, the at least one additional therapeutic agent is triheptanoin (triheptanoin), n-heptanoic acid, triglycerides, or salts thereof, or a combination thereof.
In some embodiments, the subject is a human.
Articles of manufacture are provided that include packaging material, a PPAR δ agonist compound described herein (e.g., compound 1 or a pharmaceutically acceptable salt thereof) or a pharmaceutically acceptable salt thereof within the packaging material, and a label that indicates that the PPAR δ agonist compound is useful for modulating PPAR δ activity, or for treating, preventing, or ameliorating one or more symptoms of mitochondrial myopathy.
Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.
Drawings
Figure 1 shows the effect of administering compound 1 (100 mg once daily for 12 weeks) on a12 minute walk test to a genetically diagnosed primary mitochondrial myopathy patient (mtDNA deficiency) with myopathy. 9 patients showed an improvement in the 12 minute walk test over the course of the 12 week treatment regimen.
Figure 2 shows the effect of compound 1 (100 mg once daily for 12 weeks) administration on pain scores to genetically diagnosed primary mitochondrial myopathy patients with myopathy (mtDNA deficiency). Over the course of the 12-week treatment regimen, the mean transient pain index (BPI) score for 9 patients administered compound 1 decreased.
Detailed Description
Healthy mitochondria are critical to normal cellular activity. Mitochondria collect energy in the form of ATP while regulating cellular metabolism. Mitochondria play many key roles in the cell, including oxidative phosphorylation, fatty acid oxidation (β -oxidation), central carbon metabolism, and biosynthesis of cellular growth intermediates.
The main pathway of fatty acid degradation is mitochondrial fatty acid beta-oxidation (FAO). FAOs are key metabolic pathways for energy homeostasis in organs such as liver, heart and skeletal muscle. Fatty Acid Transporters (FATP) are intact membrane proteins that enhance the uptake of long-chain and very long-chain fatty acids into cells. In the cytosol, fatty acids are activated by acyl-CoA synthetases to acyl-CoA (CoA) esters, which can then be directed to a variety of different metabolic pathways, such as lipid synthesis and FAO. FAOs require mitochondrial import of acyl-CoA. Since the mitochondrial membrane is impermeable to acyl-CoA, carnitine circulation is required for import into the mitochondria. The system requires L-carnitine and consists of two acyltransferases, carnitine palmitoyl transferase 1 and 2(CPT1 and CPT2) and carnitine acylcarnitine translocase (CACT). Within the mitochondria, acyl-CoA is degraded by β -oxidation, a cyclic process of four enzymatic steps. acyl-CoA is shortened by releasing two carboxy terminal carbon atoms as acetyl-CoA per cycle. Not only does FAO produce acetyl-CoA to fuel the Krebs cycle (also known as the tricarboxylic acid (TCA) cycle) and ketogenesis, but it also reduces flavin adenine dinucleotide (to FADH2) and nicotinamide adenine dinucleotide (to NADH), and these reduced products are fed directly into the electron transport chain (respiratory chain). To be able to completely degrade fatty acids, the β -oxidation mechanism has different chain length specific enzymes.
Oxidative phosphorylation (OXPHOS) is a metabolic pathway responsible for the production of most of the cellular energy in the form of ATP. The OXPHOS pathway includes complex I-IV and complex V, ATP synthases of the respiratory chain. Complex I (NADH: coenzyme Q oxidoreductase) oxidizes NADH by reducing coenzyme Q10 (also known as CoQ) from its ubiquinone (CoQ; Q) form to ubiquinol (QH2), thereby creating an electrochemical gradient across the inner mitochondrial membrane. Complex II (succinate-CoQ oxidoreductase) associates the krebs cycle (also known as the tricarboxylic acid (TCA) cycle) with the respiratory chain in an intricate and complex manner. Complex II oxidizes succinic acid by reducing CoQ from its ubiquinone (CoQ; Q) form to ubiquinol (QH 2). Complex III (ubiquinol-cytochrome c oxidoreductase) catalyzes the reduction of cytochrome c by oxidation of ubiquinol and generates an electrochemical gradient. Complex IV (cytochrome c oxidase) is responsible for the terminal enzymatic reaction of the respiratory chain, which transfers an electron (e-) to molecular oxygen and creates an electrochemical gradient. Complex V converts the transmembrane electrochemical proton (H +) gradient energy into mechanical energy, which catalyzes the chemical bond energy between ADP and phosphate (P) to form ATP.
Healthy mitochondrial function requires more than 1,500 proteins, 13 of which are encoded by mitochondrial dna (mtdna) and the remainder by the nucleus (nDNA). Approximately 100 proteins are directly involved in oxidative phosphorylation and ATP production. Mutations in the nDNA or mtDNA genes that disrupt mitochondrial function result in a devastating mitochondrial disease known as Primary Mitochondrial Myopathy (PMM). In patients with mtDNA mutations, inheritance and clinical manifestations are further complicated by the presence of multiple mtDNA genomes in a single cell, resulting in a mixture of mutant and wild-type genomes (heterogeneity) in the same cell or tissue.
Many common mitochondrial disorders are associated with dysfunction of the OXPHOS pathway. Such dysfunctions may include defects in the activity of the OXPHOS complex and/or a decrease in the steady state level of the OXPHOS complex leading to decreased ATP production or a combination thereof (Nsihia-Sefaa, A and McKenzie, M, (2016), biosci. Rep.,36, e00313, doi:10.1042/BSR 20150295). The defects that lead to these conditions may be caused by: 1) a genetic mutation in a protein subunit encoding an OXPHOS protein; 2) mutation of a protein required for OXPHOS complex biogenesis; or 3) mutation of a protein necessary for replication, transcription and translation of mtDNA (the same as above). The OXPHOS complex and FAO pathways are biochemically relevant because NAD and FADH2 generated during FAO transfer their electrons to the OXPHOS complex. Studies have shown that primary disorders in one pathway lead to secondary defects in another pathway (supra).
Since mitochondria are a major source of energy production in mammalian cells, the clinical features of primary mitochondrial myopathy typically involve tissues with the highest energy demand. Furthermore, mtDNA is present in all human tissues, which means that dysfunction occurs in multi-organ systems. The organ systems most commonly affected are the nervous, muscular, cardiac and endocrine systems. Primary mitochondrial myopathies are often progressive conditions that produce significant disability, and in some cases premature death, often due to cardiac or nervous system involvement, such as arrhythmias or epilepsy. Myopathy may be the only clinical feature of mitochondrial disease, but may also be a component of other mitochondrial diseases or disorders
PPAR δ is the most abundant PPAR subtype in skeletal muscle, and is more highly expressed in oxidized type I muscle fibers than in glycolytic type II muscle fibers. Both short-term exercise and endurance training result in increased PPAR δ expression in skeletal muscle of humans and rodents. Rodent studies have shown that one key feature of PPAR δ activation is the induction of skeletal muscle fatty acid oxidation. Upon activation of PPAR δ in mouse skeletal muscle, fiber composition changes to oxidative form I, inducing fatty acid oxidation, mitochondrial respiration, oxidative metabolism, and slow contraction of the muscle contractile organs. In addition to the metabolic effects of PPAR delta activation, PPAR delta also stimulates peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha), an effect that is associated with mitochondrial biogenesis. This type of adaptation is identical to that observed in response to physical exercise, in fact, transgenic (Tg) overexpressing mice for PPAR δ showed increased running endurance (Wang et al, PLoS biol.2: e294 (2004)).
Management of patients with mitochondrial disease focuses on strategies to reduce morbidity and mortality as well as early treatment of organ-specific complications. Primary mitochondrial myopathy represents a significant unmet medical need area; there is currently no available disease modifying therapy for patients with primary mitochondrial myopathy.
In some embodiments, described herein are methods and compositions for treating a primary mitochondrial myopathy in a mammal comprising administering a PPAR δ agonist compound to a mammal having a primary mitochondrial myopathy. Further described herein, in some embodiments, are methods and compositions for modulating PPAR δ in a mammal having a primary mitochondrial myopathy comprising administering a PPAR δ agonist compound to a mammal having a primary mitochondrial myopathy. In some embodiments, modulating PPAR δ in a mammal with a primary mitochondrial myopathy results in an improvement in one or more symptoms associated with the primary mitochondrial myopathy. In some embodiments, the mammal is a human.
In some embodiments, the mammal having the primary mitochondrial myopathy has been diagnosed with Kearns-Sayre syndrome (KSS), Leigh syndrome, Maternally Inherited Leigh Syndrome (MILS), mitochondrial DNA depletion syndrome (MDS), mitochondrial encephalomyopathy, lactic acidosis and stroke-like attacks (MELAS), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with fragmented red fibers (MERRF), neuroataxia and retinitis pigmentosa (NARP), Pearson syndrome, or progressive extraocular muscular Palsy (PEO).
In some embodiments, the mammal having the primary mitochondrial myopathy further comprises a secondary mitochondrial myopathy. In some embodiments, secondary mitochondrial myopathy refers to any abnormal mitochondrial function other than that caused by primary mitochondrial myopathy (see, e.g., D.Niyazov et al, Molecular dynamics 2016; 7; 122- & 137).
In some embodiments, the secondary mitochondrial myopathy is a hereditary secondary mitochondrial myopathy. In some embodiments, the secondary mitochondrial myopathy involves a mutation in a non-OXPHOS gene. In some embodiments, the secondary mitochondrial myopathy involves a secondary defect in OXPHOS function caused by a primary FAO defect. In some embodiments, the secondary mitochondrial myopathy results from a primary OXPHOS deficiency that results in a secondary FAO disease. In some embodiments, the secondary mitochondrial myopathy is an acquired secondary mitochondrial myopathy. For example, acquired secondary mitochondrial myopathy is the result of environmental factors that cause oxidative stress, including but not limited to aging, inflammation, and mitotic drugs (mitotic drugs). In some embodiments, the mitochondrially toxic drug includes a corticosteroid, valproic acid, phenytoin, barbiturates, propofol, a volatile anesthetic, a non-depolarizing muscle relaxant, a local anesthetic, a statin, a fibrate, a biguanide, a glitazone, a beta-blocker, amiodarone, a neuroleptic, an antibiotic, or a chemotherapeutic drug. In some embodiments, the chemotherapeutic agent is doxorubicin or a platinum-based chemotherapeutic agent such as cisplatin.
In some embodiments, described herein are methods and compositions for treating a mammal with a PPAR δ agonist, wherein the PPAR δ agonist activates PPAR δ. In some embodiments, the PPAR δ agonist increases PPAR δ expression. In some embodiments, the PPAR δ agonist increases the activity of PPAR δ. In some embodiments, the PPAR δ agonist increases the expression or activity of a gene involved in mitochondrial function or a protein thereof. In some embodiments, the gene is a nuclear dna (ndna) gene. In some embodiments, the gene is a mitochondrial dna (mtdna) gene.
In some embodiments, the PPAR δ agonist increases the expression or activity of a nddna gene, including but not limited to NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NDUFA1, NDUFA2, NDUFA9, NDUFAF 9, ndaf 9, ndb 9, SDHA, SDHB, SDHC, SDHD, SDHAF 9, UQCRB, BCS 19, UQCRQ, UQCRC 9, opcyc 9, TTC 9, ly3672, UQCC 9, uxc 9, prfcx 9, ptx 9, ptfac 9, phs 9, phc 9, p 9, tfp 9, tforc 9, tfp 9, tfa 9, tforc 9, tff 9, 363636363672, 9, 363636363672, 36363636363636363636363672, 3636363672, 9, 36363636363636363672, 363636363672, 9, 363636363636363636363636363636363636363636363672, 9, 363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363672, 9, 36363672, 9, 36363636363636363672, 9, 36363636363636363636363636363636363636363636363672, 363636363672, 9, 36363672, 9, 3636363672, 363636363636363636363636363636363636363636363636363636363636363636363636363636363672, 3636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363672, 363636363636363636363636363636363636363636363636363636363636363636363636363636363672, 363636363636363636363636363636363636363636363672, 3636363636363636363636363636363636363672, 9, 363636363636363636363636363636363636363636363636363636363672, 9, 36363636363636363636363636363672, 36363636363672, 36363672, 3636363636363636363672, 9, 363672, 9, 363636363636363636363636363636363636363672, 9, 363672, 9, 36363672, 9, 36363636363636363636363636363636, TK2, TYMP, MGME1, SUCLG1, SUCLA2, RNASEH1, C10orf2, POLG2, DNA2, RRM2B, FBXL4, AFG3L2, SPG7, and ANT 1.
In some embodiments, the nDNA gene encodes a solute carrier for Complex I (NADH: ubiquinone oxidoreductase), Complex II (succinate dehydrogenase), Complex III (CoQ-cytochrome c reductase), Complex IV (cytochrome c oxidase), Complex V (ATP synthase), aminoacyl-tRNA synthetase, Release factor, elongation factor, mitochondrial ribosomal protein, thiamine, and phosphate, or a combination thereof. In some embodiments, the gene encoding complex I comprises ndifs 1, ndifs 2, ndifs 3, ndifs 4, ndifs 6, ndifs 7, ndifs 8, ndifv 1, ndifv 2, ndifa 1, ndifa 2, ndifa 9, ndifa 10, ndifa 11, ndifa 12, ndifa 13, ndifa 2, ndifa 6, or ndifb 11. In some embodiments, the gene encoding complex II comprises SDHA, SDHB, SDHC, SDHD, or SDHAF 1. In some embodiments, the gene encoding complex III comprises UQCRB, BCS1L, UQCRQ, UQCRC2, CYC1, TTC19, LYRM7, UQCC2, or UQCC 3. In some embodiments, the gene encoding complex IV comprises COA5, SURF1, COX10, COX14, COX15, COX20, COX6B1, FASTKD2, SCO1, SCO2, LRPPRC, TACO1, or PET 100. In some embodiments, the gene encoding complex V comprises ATPAF2, TMEM70, ATP5E, or ATP5a 1. In some embodiments, the gene encoding the aminoacyl-tRNA synthetase comprises AARS2, DARS2, EARS2, RARS2, YARS2, FARS2, HARS2, LARS2, VARS2, TARS2, IARS2, CARS2, PARS2, NARS2, KARS, GARS, SARS2, or MARS 2. In some embodiments, the gene encoding a release factor comprises C12orf 65. In some embodiments, the gene encoding an elongation factor comprises TUFM, TSFM, or GFM 1.
In some embodiments, the gene encoding a mitochondrial ribosomal protein comprises MRPS16, MRPS22, MRPL3, MRP12, or MRPL 44. In some embodiments, the solute-loaded genes encoding thiamine and phosphate comprise SLC19A3, SLC25A3, or SLC25a 19.
In some embodiments, the nDNA gene is involved in phospholipid metabolism, toxic compound metabolism, disulfide-bond relay systems, ferritin assembly, tRNA modification, mRNA processing, mitochondrial fusion or fission, deoxynucleotide triphosphate synthesis, protein quality control and degradation, ATP and ADP transport, or a combination thereof. In some embodiments, the gene involved in phospholipid metabolism comprises AGK, SERAC1, or TAZ. In some embodiments, the genes involved in toxic compound metabolism include HIBCH, ECHS1, ete 1, or MPV 17. In some embodiments, the gene involved in the disulfide relay system comprises GFER. In some embodiments, the genes involved in ferrithioprotein assembly include ISCU, BOLA3, NFU1, or IBA 57. In some embodiments, the gene involved in tRNA modification comprises MTO1, GTP3BP, TRMU, PUS1, MTFMT, TRIT1, TRNT1, or TRMT 5. In some embodiments, the genes involved in mRNA processing include LRPPRC, TACO1, ELAC2, PNPT1, HSD17B10, MTPAP, or PTCD 1. In some embodiments, the genes involved in mitochondrial fusion and fission include OPA1 or MFN 2. In some embodiments, the genes involved in deoxynucleotide triphosphate synthesis include DGUOK, TK2, TYMP, MGME1, SUCLG1, SUCLA2, RNASEH1, C10orf2, POLG2, DNA2, or RRM 2B. In some embodiments, genes involved in protein quality control and degradation include FBXL4, AFG3L2, or SPG 7. In some embodiments, the genes involved in ATP and ADP transport include ANT 1.
In some embodiments, described herein are methods and compositions for treating a mammal with a PPAR δ agonist, wherein the PPAR δ agonist increases the expression or activity of a mitochondrial dna (mtdna) gene. In some embodiments, the mtDNA gene comprises at least one mutation, deletion, defect, or combination thereof. In some embodiments, the at least one mutation in the at least one mitochondrial dna (mtdna) gene comprises a mutation selected from the group consisting of m.3243a > G, m.8344a > G, m.8993t > G, m.13513g > a, m.11778g > a, m.14484t > C, and combinations thereof. In some embodiments, the at least one mutation in the at least one mitochondrial dna (mtdna) gene comprises the mutation m.3243a > G. In some embodiments, the mtDNA gene comprises a mutation selected from the group consisting of an 8284bp deletion, a 6277bp deletion, a 4977bp deletion, and combinations thereof.
In some embodiments, the PPAR δ agonist increases the percentage of non-mutated mitochondrial dna (mtdna). In some embodiments, the PPAR δ agonist increases the percentage of unmutated mtDNA by at least or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, or greater than 95%. In some embodiments, the PPAR δ agonist increases the percentage of unmutated mtDNA in the range of about 10% to about 90%, about 20% to about 80%, about 30% to about 70%, or about 40% to about 60%. In some embodiments, the PPAR δ agonist increases the percentage of mtDNA that is unmutated such that the proportion of mtDNA in the cell is substantially unmutated. In some embodiments, the ratio of unmutated mtDNA to mutated mtDNA in the cell is at least or about 1.25:1, 1.5:1, 1.75:1, 2.0:1, 2.5:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, or greater than 10: 1.
In some embodiments, the PPAR δ agonist increases mitochondrial biogenesis. In some embodiments, the PPAR δ agonist increases the expression or activity of a gene involved in mitochondrial biogenesis or a protein thereof. In some embodiments, the PPAR δ agonist increases transcription of a gene involved in mitochondrial biogenesis. In some embodiments, the PPAR δ agonist increases translation of a protein involved in mitochondrial biogenesis. In some embodiments, the protein is a transcription factor. In some embodiments, the protein is peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1 alpha).
In some embodiments, a PPAR delta agonist described herein modulates the expression or activity of PGC-1 alpha. In some embodiments, the PPAR δ agonist increases transcription of the proliferator-activated receptor γ coactivator 1- α gene. In some embodiments, the PPAR delta agonist increases the translation of the PGC-1 alpha protein. In some embodiments, the PPAR delta agonist modulates post-translational modifications of PGC-1 alpha. For example, PPAR δ agonists modulate PGC-1 α phosphorylation, acetylation, deacetylation, sumoylation, ubiquitination, O-linked β -N-acetylglucosaminylation, methylation, or combinations thereof.
In some embodiments, the PPAR δ agonist decreases the rate of decrease in mitochondrial biogenesis. In another embodiment, described herein is a method of increasing mitochondrial biogenesis in one or more tissues of a mammal relative to a control, wherein the increase in mitochondrial biogenesis comprises comparing one or more measurements of mitochondrial biogenesis in the mammal after treatment with a PPAR δ agonist to a baseline measurement of mitochondrial biogenesis in the same mammal. In some embodiments, the tissue of the mammal comprises muscle tissue. In another embodiment, reducing the increased rate of mitochondrial biogenesis in the mammal comprises returning to a baseline measurement of mitochondrial biogenesis in the mammal more quickly than a control. In further embodiments, increasing the decreased rate of mitochondrial biogenesis in the mammal comprises returning to a baseline measurement of mitochondrial biogenesis in the mammal after a period of time that is less than 95%, or less than 90%, or less than 85%, or less than 80%, or less than 75%, or less than 70%, or less than 65%, or less than 60%, or less than 55%, or less than 50% of the time that the control returns to baseline. In another embodiment, the increase in mitochondrial biogenesis in the mammal is greater than the increase in mitochondrial biogenesis relative to a control. In another embodiment, the increase in mitochondrial biogenesis in the mammal relative to a baseline measurement of mitochondrial biogenesis in the mammal prior to treatment with the PPAR δ agonist comprises an increase in mitochondrial biogenesis of greater than 1%, greater than 2%, greater than 3%, greater than 4%, greater than 5%, greater than 6%, greater than 7%, greater than 8%, greater than 9%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, or greater than 50%.
Muscle tissue is soft tissue containing muscle cells found in most animals. Muscle cells contain protein filaments that slide over each other and cause contraction, thereby changing the length and shape of the muscle cell. The function of muscles is to produce strength and movement. The body has three types of muscles: a) skeletal muscle (the muscle responsible for moving the limbs and the areas outside the body); b) cardiac muscle (muscle of the heart); c) smooth muscle (muscle located in the arterial and intestinal walls).
As used herein, the term "muscle cell" refers to any cell that contributes to muscle tissue. Myoblasts, satellite cells, myotubes, and myofibrillar tissue are all included within the term "muscle cells" and can all be treated using the methods described herein. Muscle cell effects can be induced in skeletal, cardiac and smooth muscle.
Skeletal or voluntary muscles are usually anchored to the bone through tendons and are often used to influence skeletal movement, such as moving or maintaining posture. Although some control of the skeletal muscle is usually maintained as an involuntary reflex (e.g., postural muscle or diaphragm), the skeletal muscle reacts to conscious control. Smooth or involuntary muscles are located within the walls of organs and structures such as the esophagus, stomach, intestine, uterus, urethra and blood vessels. Unlike skeletal muscle, smooth muscle is not conscious. The myocardium is also an involuntary muscle, but more similar in structure to skeletal muscle, and is present only in the heart. The cardiac and skeletal muscles have striations because they contain muscle segments that are assembled into a highly regular, fasciculate arrangement. In contrast, myofibrils of smooth muscle cells are not arranged in muscle nodes and thus have no striations.
Skeletal muscle is further divided into two major types: type I (or "slow contraction muscle") and type II (or "fast contraction muscle"). Type I muscle fibers have dense capillaries and are rich in mitochondria and myoglobin, which gives the characteristic red color to type I muscle tissue. Type I muscle fibers can carry more oxygen and use fat or carbohydrates as fuel to maintain aerobic activity. Type I muscle fibers contract for a long time but with little strength. Type II muscle fibers can be subdivided into three major subtypes (IIa, IIx and IIb), which differ in their contraction speed and the force produced. Type II muscle fibers contract rapidly and forcefully, but fatigue quickly, thus producing only a brief anaerobic explosive activity before the muscle contraction becomes painful.
Biogenesis of mitochondria is measured by mitochondrial mass and volume via tissue section staining using fluorescently labeled antibodies specific for oxidative phosphorylation complexes, such as anti-oxphosx complex Vd subunit antibodies from Life Technologies, or using mitochondrial specific dyes in live cell staining, such as the Mito-tracker probe from Life Technologies. Mitochondrial biogenesis can also be measured by monitoring gene expression of one or more transcription factors associated with mitochondrial biogenesis (e.g., PGC1 α, NRF1, or NRF2) using techniques such as QPCR.
FAOs are critical for ATP production in muscle mitochondria, especially during exercise, by providing substrates for the respiratory chain. The source of fatty acids varies with exercise intensity, with the contribution of free fatty acids increasing with exercise intensity. Mutations in any of the enzymes involved in FAO can lead to various clinical symptoms, particularly during fasting and in organs that require high energy. During infancy, patients may develop cardiac symptoms such as dilated or hypertrophic cardiomyopathy and/or arrhythmia. Alternatively, FAO deficiency may manifest as a mild, later ("adult") onset disease characterized by exercise-induced myopathy and rhabdomyolysis.
PPARs (PPAR- α, PPAR- δ, PPAR- γ) are known for their transcriptional regulation of FAO. Activation of the PPAR can trigger up-regulation of gene expression of FAO-involved enzymes, leading to an increase in residual enzyme activity, thus correcting the FAO flux in the treated cells. In a study using cultured patient muscle cells, specific agonists of PPAR δ (GW 072) and PPAR α (GW7647) (to a lesser extent) stimulated FAO in control myoblasts (Djouadi, f. et al, j.clin.endocrinol.metab.90, 1791-1797,2005).
In vitro studies with compound 1 have demonstrated its ability to induce a dose-dependent increase in fatty acid oxidation in human and rat muscle cell lines. In addition, compound 1 treatment altered the expression pattern of a number of known PPAR δ regulatory genes in pathways important for fatty acid metabolism in vivo (CPT1b) and mitochondrial biogenesis (PGC1 α).
In some embodiments, the deficiency in FAO capability is measured by comparing the FAO capability of a mammal identified as having a primary mitochondrial myopathy to the FAO capability of a mammal without a primary mitochondrial myopathy (i.e., a control). In some embodiments, described herein are methods of increasing FAO capability in a mammal having a primary mitochondrial myopathy, comprising administering a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) to a mammal having a primary mitochondrial myopathy. In some embodiments, described herein are methods of increasing FAO capacity in a mammal having a primary mitochondrial myopathy by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 75%, about 80%, about 95%, about 100%, or greater than 100% of the level observed for a mammal not having a primary mitochondrial myopathy. In some embodiments, described herein are methods of increasing FAO capacity in a mammal having a primary mitochondrial myopathy to a level substantially similar to that observed for a mammal not having a primary mitochondrial myopathy, comprising administering a PPAR δ agonist compound (e.g., compound 1, or a pharmaceutically acceptable salt thereof) to a mammal having a primary mitochondrial myopathy. In some embodiments, described herein are methods of restoring (i.e., normalizing by improving or increasing) FAO capacity in a mammal having a primary mitochondrial myopathy to a substantially similar level to that observed in a mammal not having a primary mitochondrial myopathy, comprising administering a PPAR δ agonist compound (e.g., compound 1, or a pharmaceutically acceptable salt thereof) to a mammal having a primary mitochondrial myopathy.
In some embodiments, administration of a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) to a mammal with primary mitochondrial myopathy restores (i.e., normalizes by increasing) the lack of activity of one or more enzymes or proteins involved in the fatty acid β -oxidation pathway. In some embodiments, restoring activity comprises increasing activity to a substantially similar level observed in a mammal without primary mitochondrial myopathy.
In some aspects, a PPAR δ agonist compound is administered to a subject (e.g., a human) in a therapeutically effective amount. As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of active ingredient that elicits the desired biological or medical response, e.g., alleviation or alleviation of the symptoms of the condition being treated. In some embodiments of the invention, the amount of PPAR δ agonist compound administered depends on various factors including, but not limited to, the weight of the subject, the nature and/or extent of the subject's condition, and the like.
Compound (I)
PPAR δ agonist compounds are fatty acids, lipids, proteins, peptides, small molecules or other chemical entities that bind to cellular PPAR δ and, without being bound by any particular theory, trigger a downstream response, i.e., gene transcription (either natural gene transcription or reporter construct gene transcription), equivalent to an endogenous ligand such as retinoic acid, or equivalent to a standard reference PPAR δ agonist compound such as carbacycline (carbacycline).
In embodiments, the PPAR δ agonist compound is a selective agonist. As used herein, a selective PPAR δ agonist compound is considered a chemical entity that binds to and activates cellular PPAR δ and does not substantially activate cellular peroxisome proliferator-activated receptors- α (PPAR α) and- γ (PPAR γ). As used herein, a selective PPAR δ agonist compound is a chemical entity that has at least 10-fold maximal activation (compared to endogenous receptor ligands), wherein PPAR δ is activated at greater than 100-fold efficacy relative to either or both of PPAR α and PPAR γ. In a further embodiment, the selective PPAR δ agonist compound is a chemical entity that binds to and activates PPAR δ in human cells and does not substantially activate either or both of human PPAR α and PPAR γ. In further embodiments, the selective PPAR δ agonist compound is a chemical entity that activates PPAR δ at a potency of at least about 10-fold, or about 20-fold, or about 30-fold, or about 40-fold, or about 50-fold, or about 100-fold relative to either or both of PPAR α and PPAR γ.
In some embodiments, selective PPAR δ agonist compounds contemplated herein are capable of contacting amino acid residues at both VAL312 and ILE328(hPPAR δ numbering) positions of PPAR δ. In some embodiments, the selective PPAR δ agonist compound is capable of contacting amino acid residues at VAL298, LEU303, VAL312, and ILE328(hPPAR δ numbering) simultaneously.
"activation" is defined herein as the downstream response described above, in the case of PPARs, gene transcription. In some cases, gene transcription is measured indirectly as the downstream production of proteins that reflect activation of the particular PPAR subtype studied. Alternatively, in some cases, artificial reporter constructs were used to study the activation of individual PPARs expressed in cells. In some cases, the ligand binding domain of the particular receptor to be studied is fused to the DNA binding domain of a transcription factor (e.g., yeast GAL4 transcription factor DNA binding domain) that produces convenient laboratory readings. In some cases, the fusion protein is transfected into a laboratory cell line with the Gal4 enhancer, which affects luciferase protein expression. When such a system is transfected into a laboratory cell line, binding of the receptor agonist to the fusion protein will result in light emission.
In some embodiments, the selective PPAR δ agonist compound exemplifies the presence of the above gene transcription profile in cells that selectively express PPAR δ, but not in cells that selectively express PPAR γ or PPAR α. In one embodiment, the cells express human PPAR δ, PPAR γ, and PPAR α, respectively.
In further embodiments, the PPAR δ agonist compounds may have an EC of less than about 5 μm50Values as determined by the PPAR transient transactivation assay described below. In one embodiment, EC50The value is less than about 1 μm. In another embodiment, EC50Values are less than about 500 nM. In another embodiment, EC50Values are less than about 100 nM. In another embodiment, EC50Values were less than about 50 nM.
In some cases, the PPAR transient transactivation assay is based on transient transfection of two plasmids encoding a chimeric test protein and a reporter protein, respectively, into human HEK293 cells. In some cases, the chimeric test protein is a fusion of the DNA Binding Domain (DBD) from the yeast GAL4 transcription factor with the Ligand Binding Domain (LBD) of a human PPAR protein. In addition to the ligand binding pocket, the PPAR-LBD moiety also has a native activation domain that enables the fusion protein to function as a PPAR ligand-dependent transcription factor. GAL4 DBD directs chimeric proteins to bind only to the GAL4 enhancer (absent in HEK293 cells). The reporter plasmid contains the Gal4 enhancer that drives the expression of firefly luciferase protein. After transfection, HEK293 cells express GAL4-DBD-PPAR-LBD fusion protein. The fusion protein will in turn bind to the Gal4 enhancer, which controls luciferase expression, and do nothing without ligand. Following PPAR ligand-added cells, luciferase protein will be produced in an amount corresponding to activation of the PPAR protein. After addition of the appropriate substrate, the amount of luciferase protein is measured by light emission.
Cell culture and transfection: in some cases, HEK293 cells were grown in DMEM + 10% FCS. In some cases, cells were seeded in 96-well plates the day before transfection to achieve 50-80% confluence at the time of transfection. In some cases, 0.8mg of DNA was co-transfected per well using FuGene transfection reagent, according to manufacturer's instructions, containing 0.64mg pM1a/gLBD, 0.1mg pCMVbGal, 0.08mg pGL2(Gal4)5And 0.02mg of pADVANTAGE. In some cases, the cells were allowed to express the protein for 48 hours before the compound was added.
Plasmids: in some cases, human PPAR δ was obtained by PCR amplification using cDNA reverse transcribed from mRNA from human liver, adipose tissue, and placenta, respectively. In some embodiments, the amplified cDNA is cloned into pcr2.1 and sequenced. In some cases, the Ligand Binding Domain (LBD) for each PPAR isoform was generated by PCR (PPAR. delta.: aa 128-C terminal) and fused to the DNA Binding Domain (DBD) of the yeast transcription factor GAL4 by subcloning the in-frame fragment into the vector pM1 (Sadowski et al, (1992), Gene 118,137) to generate plasmids pM 1. alpha. LBD, pM 1. gamma. LBD, and pM 1. delta. In some cases, the fusion is subsequently verified by sequencing. In some cases, the vector is constructed by inserting an oligonucleotide encoding 5 repeats of the GAL4 recognition sequence (Webster et al, (1988), Nucleic Acids Res.16,8192)In the pGL2 promoter (Promega) in vivo, plasmid pGL2(GAL4) was generated5To construct a reporter protein. pCMVbGal is purchased from Clontech in some cases, and pADVANTAGE is purchased from Promega in some cases.
Compound (I): in some cases, compounds were dissolved in DMSO and diluted 1:1000 when added to cells. In some cases, compounds were tested in quadruplicate at concentrations ranging from 0.001 to 300 μ M. In some cases, cells were treated with compounds for 24 hours prior to luciferase assay. In some cases, each compound is tested in at least two separate experiments.
Luciferase assay: in some cases, the medium containing the test compound is aspirated, and in some cases, will contain 1mM Mg++And Ca++100 μ l PBS was added to each well. In some embodiments, luciferase assays are performed using the LucLite kit according to the manufacturer's instructions (Packard Instruments). In some cases, light emission is quantified by counting on a Packard LumiCounter. To measure β -galactosidase activity, in some cases, 25ml of supernatant from each transfection lysate was transferred to a new microplate. In some embodiments, the beta-galactosidase assay is performed in a microplate using a kit from Promega and read in a Labsystems Ascent Multiscan reader. In some cases, the β -galactosidase data was used to normalize (transfection efficiency, cell growth, etc.) the luciferase data.
Statistical method: in some cases, the activity of the compound was calculated as fold induction compared to untreated samples. In some embodiments, for each compound, efficacy (maximal activity) is given as the relative activity compared to wy14,643 for PPAR α, rosiglitazone for PPAR γ, and carbacycline for PPAR δ. EC (EC)50Is the concentration that produces 50% of the maximum observed activity. In some cases, EC was calculated by nonlinear regression using GraphPad PRISM 3.02(GraphPad Software, San Diego, CA)50The value is obtained.
In further embodiments, the PPAR δ agonist compounds have a molecular weight of less than about 1000g/mol, or less than about 950g/mol, or less than about 900g/mol, or less than about 850g/mol, or less than about 800g/mol, or less than about 750g/mol, or less than about 700g/mol, or less than about 650g/mol, or a molecular weight of less than about 600g/mol, or a molecular weight of less than about 550g/mol, or a molecular weight of less than about 500g/mol, or a molecular weight of less than about 450g/mol, or a molecular weight of less than about 400g/mol, or a molecular weight of less than about 350g/mol, or a molecular weight of less than about 300g/mol, or a molecular weight of less than about 250 g/mol. In another embodiment, the PPAR Δ agonist compound has a molecular weight of greater than about 200g/mol, or a molecular weight of greater than about 250g/mol, or a molecular weight of greater than about 300g/mol, or a molecular weight of greater than about 350g/mol, or a molecular weight of greater than about 400g/mol, or a molecular weight of greater than about 450g/mol, or a molecular weight of greater than about 500g/mol, or a molecular weight of greater than about 550g/mol, or a molecular weight of greater than about 600g/mol, or a molecular weight of greater than about 650g/mol, or a molecular weight of greater than about 700g/mol, or a molecular weight of greater than about 750g/mol, or a molecular weight of greater than about 800g/mol, or a molecular weight of greater than about 850g/mol, or a molecular weight of greater than about 900g/mol, Or a molecular weight greater than about 950g/mol, or a molecular weight greater than about 1000 g/mol. In some embodiments, any of the upper and lower limits described above in this paragraph are combined.
In some embodiments, the PPAR δ agonist compound is a PPAR δ agonist compound disclosed in any of the following published patent applications: WO 97/027847, WO 97/027857, WO 97/028115, WO 97/028137, WO 97/028149, WO 98/027974, WO 99/004815, WO 2001/000603, WO 2001/025181, WO 2001/025226, WO 2001/034200, WO 2001/060807, WO 2001/079197, WO 2002/014291, WO 2002/028434, WO 2002/046154, WO 2002/050048, WO 2002/059098, WO 2002/062774, WO 2002/070011, WO 2002/076957, WO 2003/016291, WO 2003/024395, WO 2003/033493, WO 2003/035603, WO 2003/072100, WO 2003/074050, WO 2003/074051, WO 2003/074052, WO 2003/074495, WO 2003/084916, WO 2003/097607, WO 2004/000315, WO 2004/000762, WO 2004/005253, WO 2004/037776, WO 2004/060871, WO 2004/063165, WO 2004/063166, WO 2004/073606, WO 2004/080943, WO 2004/080947, WO 2004/092117, WO 2004/092130, WO 2004/093879, WO 2005/060958, WO 2005/097098, WO 2005/097762, WO 2005/097763, WO 2005/115383, WO 2006/055187, WO 2007/003581 and WO2007/071766 (wherein these PPAR δ agonist compounds of each are incorporated herein).
In some embodiments, the PPAR δ agonist compound is a PPAR δ agonist compound disclosed in any of the following published patent applications: WO 2014/165827; WO 2016/057660; WO 2016/057658; WO 2017/180818; WO 2017/062468; and WO/2018/067860 (wherein each of these PPAR δ agonist compounds is incorporated herein).
In some embodiments, the PPAR δ agonist compound is a PPAR δ agonist compound disclosed in any of the following published patent applications: U.S. patent application publication nos. 20160023991, 20170226154, 20170304255 and 20170305894 (these PPAR δ agonist compounds of each are incorporated herein).
In some embodiments, the PPAR δ agonist compound is a phenoxyalkylcarboxylic acid compound. In some embodiments, the phenoxyalkyl carboxylic acid compound is a 2-methylphenoxyalkylcarboxylic acid compound.
In some embodiments, the PPAR δ agonist compound is a phenoxyalkylcarboxylic acid compound, i.e., a phenoxyacetic acid compound, a phenoxypropionic acid compound, a phenoxyacrylic acid compound, a phenoxybutyric acid compound, a phenoxybutenoic acid compound, a phenoxyvaleric acid compound, phenoxypentenoic acid compound, phenoxyhexanoic acid compound, phenoxyhexenoic acid compound, phenoxyoctanoic acid compound, phenoxyoctenoic acid compound, phenoxynonanoic acid compound, phenoxynonenoic acid compound, phenoxydecanoic acid compound, or phenoxydecenoic acid compound. In some embodiments, the PPAR δ agonist compound is a phenoxyacetic acid compound or a phenoxyhexanoic acid compound. In some embodiments, the PPAR δ agonist compound is a phenoxyacetic acid compound. In some embodiments, the phenoxyacetic acid compound is a 2-methylphenoxyacetic acid compound. In some embodiments, the PPAR δ agonist compound is a phenoxyhexanoic acid compound.
In some embodiments, the PPAR δ agonist compound is a phenoxyacetic acid compound, a((benzamidomethyl) phenoxy) hexanoic acid compound, a ((heteroarylmethyl) phenoxy) hexanoic acid compound, a methylthiophenoxyacetic acid compound, or an allyloxyphenoxyacetic acid compound.
In some embodiments, the PPAR δ agonist compound is a ((benzamidomethyl) phenoxy) hexanoic acid compound.
In some embodiments, the PPAR δ agonist compound is a ((heteroarylmethyl) phenoxy) hexanoic acid compound. In some embodiments, the PPAR δ agonist compound is a ((imidazolylmethyl) phenoxy) hexanoic acid compound. In some embodiments, the PPAR δ agonist compound is an imidazol-1-ylmethylphenoxyhexanoic acid compound. In some embodiments, the PPAR δ agonist compound is 6- (2- ((2-phenyl-1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid.
In some embodiments, the PPAR δ agonist compound is an allyloxyphenoxyacetic acid compound. In some embodiments, the allyloxyphenoxyacetic acid compound is a 4-allyloxy-2-methylphenoxy) acetic acid compound.
In some embodiments, the PPAR δ agonist compound is a methylthiophenoxyacetic acid compound. In some embodiments, the PPAR δ agonist compound is a 4- (methylthio) phenoxy) acetic acid compound.
In some embodiments, the PPAR δ agonist compound is a phenoxyalkylcarboxylic acid compound selected from the group consisting of: (Z) - [ 2-methyl-4- [3- (4-methylphenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -phenoxy ] acetic acid; (E) - [ 2-methyl-4- [3- [4- [3- (pyrazol-1-yl) prop-1-ynyl ] phenyl ] -3- (4-trifluoromethylphenyl) -allyloxy ] phenoxy ] acetic acid; (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid (compound 1); (E) - [ 2-methyl-4- [3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] -3- (4-trifluoromethylphenyl) allyloxy ] -phenoxy ] acetic acid; (E) -4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid; (E) - [4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methylphenyl ] -propionic acid; {4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -benzylsulfanyl ] -2-methyl-phenoxy } -acetic acid; {4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -phenylthio ] -2-methyl-phenoxy } -acetic acid; and {4- [3, 3-bis- (4-bromo-phenyl) -allyloxy ] -2-methyl-phenoxy } -acetic acid; (R) -3-methyl-6- (2- ((5-methyl-2- (4- (trifluoromethyl) phenyl) -1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid; (R) -3-methyl-6- (2- ((5-methyl-2- (6- (trifluoromethyl) pyridin-3-yl) -1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid; (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid (compound 1); 2- {4- [ ({2- [ 2-fluoro-4- (trifluoromethyl) phenyl ] -4-methyl-1, 3-thiazol-5-yl } methyl) thio ] -2-methylphenoxy } -2-methylpropionic acid (soglitazar; GW 677954); 2- [ 2-methyl-4- [ [ 3-methyl-4- [ [4- (trifluoromethyl) phenyl ] methoxy ] phenyl ] thio ] phenoxy ] -acetic acid; 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] methyl ] thio ] phenoxy ] -acetic acid (GW-501516); [4- [ [ [2- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -4-methyl-5-thiazolyl ] methyl ] thio ] -2-methylphenoxy ] acetic acid (GW0742, also known as GW 610742); 2- [2, 6-dimethyl-4- [3- [4- (methylthio) phenyl ] -3-oxo-1 (E) -propenyl ] phenoxy ] -2-methylpropanoic acid (elafinidor; GFT-505); { 2-methyl-4- [ 5-methyl-2- (4-trifluoromethyl-phenyl) -2H- [1,2,3] triazol-4-ylmethylsulfanyl ] -phenoxy } -acetic acid; and [4- ({ (2R) -2-ethoxy-3- [4- (trifluoromethyl) phenoxy ] propyl } thio) -2-methylphenoxy ] acetic acid (seladelpar; MBX-8025); (S) -4- [ cis-2, 6-dimethyl-4- (4-trifluoromethoxy-phenyl) piperazine-1-sulfonyl ] -indan-2-carboxylic acid or its tosylate salt (KD-3010); (2s) -2- { 4-butoxy-3- [ ({ [ 2-fluoro-4- (trifluoromethyl) phenyl ] carbonyl } amino) methyl ] benzyl } butanoic acid (TIPP-204); [4- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy ] phenoxy ] acetic acid (L-165,0411); 2- (4- {2- [ (4-chlorobenzoyl) amino ] ethyl } phenoxy) -2-methylpropanoic acid (bezafibrate); or a pharmaceutically acceptable salt thereof.
In another embodiment, the PPAR δ agonist compound is a 2-methylphenoxyalkylcarboxylic acid compound selected from the group consisting of: (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid (compound 1); 2- {4- [ ({2- [ 2-fluoro-4- (trifluoromethyl) phenyl ] -4-methyl-1, 3-thiazol-5-yl } methyl) thio ] -2-methylphenoxy } -2-methylpropionic acid (soglitazar; GW 677954); 2- [ 2-methyl-4- [ [ 3-methyl-4- [ [4- (trifluoromethyl) phenyl ] methoxy ] phenyl ] thio ] phenoxy ] -acetic acid; 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] methyl ] thio ] phenoxy ] -acetic acid (GW-501516); [4- [ [ [2- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -4-methyl-5-thiazolyl ] methyl ] thio ] -2-methylphenoxy ] acetic acid (GW0742, also known as GW 610742); 2- [2, 6-dimethyl-4- [3- [4- (methylthio) phenyl ] -3-oxo-1 (E) -propenyl ] phenoxy ] -2-methylpropanoic acid (elafinidor; GFT-505); { 2-methyl-4- [ 5-methyl-2- (4-trifluoromethyl-phenyl) -2H- [1,2,3] triazol-4-ylmethylsulfanyl ] -phenoxy } -acetic acid; and [4- ({ (2R) -2-ethoxy-3- [4- (trifluoromethyl) phenoxy ] propyl } thio) -2-methylphenoxy ] acetic acid (seladelpar; MBX-8025).
In another embodiment, the PPAR δ agonist compound is a compound selected from the group consisting of: (S) -4- [ cis-2, 6-dimethyl-4- (4-trifluoromethoxy-phenyl) piperazine-1-sulfonyl ] -indan-2-carboxylic acid or its tosylate salt (KD-3010); (2s) -2- { 4-butoxy-3- [ ({ [ 2-fluoro-4- (trifluoromethyl) phenyl ] carbonyl } amino) methyl ] benzyl } butanoic acid (TIPP-204); [4- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy ] phenoxy ] acetic acid (L-165,0411); and 2- (4- {2- [ (4-chlorobenzoyl) amino ] ethyl } phenoxy) -2-methylpropanoic acid (bezafibrate).
In another embodiment, the PPAR δ agonist compound is a compound selected from the group consisting of: soglitazar; lobeglitazone (lobeglitazone); nateglinide (netoglitazone); and isaglitazone (isaglitazone); 2- (4- {2- [ (4-chlorobenzoyl) amino ] ethyl } phenoxy) -2-methylpropanoic acid (bezafibrate); 2- [ 2-methyl-4- [ [ 3-methyl-4- [ [4- (trifluoromethyl) phenyl ] methoxy ] phenyl ] thio ] phenoxy ] -acetic acid (see WO 2003/024395); (S) -4- [ cis-2, 6-dimethyl-4- (4-trifluoromethoxy-phenyl) piperazine-1-sulfonyl ] -indan-2-carboxylic acid or its tosylate salt (KD-3010); (2s) -2- { 4-butoxy-3- [ ({ [ 2-fluoro-4- (trifluoromethyl) phenyl ] carbonyl } amino) methyl ] benzyl } butanoic acid (TIPP-204); 2- [ 2-methyl-4- [ [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] methyl ] thio ] phenoxy ] -acetic acid (GW-501516); 2- [2,6 dimethyl-4- [3- [4- (methylthio) phenyl ] -3-oxo-1 (E) -propenyl ] phenoxy ] -2-methylpropanoic acid (GFT-505); { 2-methyl-4- [ 5-methyl-2- (4-trifluoromethyl-phenyl) -2H- [1,2,3] triazol-4-ylmethylsulfanyl ] -phenoxy } -acetic acid; and [4- ({ (2R) -2-ethoxy-3- [4- (trifluoromethyl) phenoxy ] propyl } thio) -2-methylphenoxy ] acetic acid (seladelpar; MBX-8025).
In some embodiments, the PPAR δ agonist compound is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid (compound 1):
(E) an example of the chemical synthesis of- [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid is known from example 10 of PCT application publication No. WO 2007/071766.
Compound 1 was tested against all three human PPAR subtypes (hPPAR): hPPAR α, hPPAR γ and hPPAR δ, using in vitro assays to test this activity. Compound 1 showed significantly higher selectivity for PPAR δ compared to PPAR α and PPAR γ in humans, monkeys and mice (see table 1). In some cases, compound 1 acts as a full agonist of PPAR δ, and only acts as a partial agonist of both PPAR α and PPAR γ. In some cases, compound 1 showed negligible activity against PPAR α and/or PPAR γ in a transactivation assay testing this activity.
Table 1: potency of Compound 1 in human, monkey and mouse PPAR receptor transactivation assays
In some embodiments, compound 1 does not exhibit any human retinoid X receptor (hRXR) activity nor does it exhibit activity against the nuclear receptors FXR, LXRαOr LXRβActivity of (2). As full agonists of PPAR δ and partial agonists of both PPAR α and PPAR γ.
In some embodiments, the PPAR δ agonist compound is (Z) - [ 2-methyl-4- [3- (4-methylphenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -phenoxy ] acetic acid:
an example of the chemical synthesis of (Z) - [ 2-methyl-4- [3- (4-methylphenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -phenoxy ] acetic acid can be found in example 3 of PCT application publication No. WO 2007/071766.
In some embodiments, the PPAR δ agonist compound is (E) - [ 2-methyl-4- [3- [4- [3- (pyrazol-1-yl) prop-1-ynyl ] phenyl ] -3- (4-trifluoromethylphenyl) -allyloxy ] phenoxy ] acetic acid:
(E) an example of the chemical synthesis of- [ 2-methyl-4- [3- [4- [3- (pyrazol-1-yl) prop-1-ynyl ] phenyl ] -3- (4-trifluoromethylphenyl) -allyloxy ] phenoxy ] acetic acid can be found in example 4 of PCT application publication No. WO 2007/071766.
In some embodiments, the PPAR δ agonist compound is (E) - [ 2-methyl-4- [3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] -3- (4-trifluoromethylphenyl) allyloxy ] -phenoxy ] acetic acid:
(E) an example of the chemical synthesis of- [ 2-methyl-4- [3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] -3- (4-trifluoromethylphenyl) allyloxy ] -phenoxy ] acetic acid can be found in example 20 of PCT application publication No. WO 2007/071766.
In some embodiments, the PPAR δ agonist compound is (E) - [4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid:
(E) an example of the chemical synthesis of- [4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid can be found in example 46 of PCT application publication No. WO 2007/071766.
In some embodiments, the PPAR δ agonist compound is (E) - [4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methylphenyl ] -propionic acid:
(E) an example of the chemical synthesis of- [4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methylphenyl ] -propionic acid can be found in example 63 of PCT application publication No. WO 2007/071766.
In some embodiments, the PPAR δ agonist compound is {4- [3, 3-bis- (4-bromo-phenyl) -allyloxy ] -2-methyl-phenoxy } -acetic acid:
an example of the chemical synthesis of {4- [3, 3-bis- (4-bromo-phenyl) -allyloxy ] -2-methyl-phenoxy } -acetic acid can be found in example 10 of PCT application publication No. WO 2004/037776.
In some embodiments, the PPAR δ agonist compound is {4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -benzylthio ] -2-methyl-phenoxy } -acetic acid:
an example of the chemical synthesis of {4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -benzylthio ] -2-methyl-phenoxy } -acetic acid can be found in example 9 of PCT application publication No. WO 2007/003581.
In some embodiments, the PPAR δ agonist compound is {4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -phenylthio ] -2-methyl-phenoxy } -acetic acid:
an example of the chemical synthesis of {4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -phenylthio ] -2-methyl-phenoxy } -acetic acid can be found in example 35 of PCT application publication No. WO 2007/003581.
Thus, in one embodiment, the PPAR δ agonist compound is a compound selected from the group consisting of: (Z) - [ 2-methyl-4- [3- (4-methylphenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -phenoxy ] acetic acid; (E) - [ 2-methyl-4- [3- [4- [3- (pyrazol-1-yl) prop-1-ynyl ] phenyl ] -3- (4-trifluoromethylphenyl) -allyloxy ] phenoxy ] acetic acid; (E) -4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid; (E) - [ 2-methyl-4- [3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] -3- (4-trifluoromethylphenyl) allyloxy ] -phenoxy ] acetic acid; (E) -4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid; (E) - [4- [3- (4-chlorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methylphenyl ] -propionic acid; {4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -benzylsulfanyl ] -2-methyl-phenoxy } -acetic acid; {4- [ 3-isobutoxy-5- (3-morpholin-4-yl-prop-1-ynyl) -phenylthio ] -2-methyl-phenoxy } -acetic acid; and {4- [3, 3-bis- (4-bromo-phenyl) -allyloxy ] -2-methyl-phenoxy } -acetic acid; or a pharmaceutically acceptable salt thereof.
In a further embodiment, the PPAR δ agonist compound is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the PPAR δ agonist compound is (E) - [4- [3- (4-fluorophenyl) -3- [4- [3- (morpholin-4-yl) propynyl ] phenyl ] allyloxy ] -2-methyl-phenoxy ] acetic acid sodium salt.
In a further embodiment, the PPAR δ agonist compound is compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, compound 13, compound 14, compound 15 or compound 16, disclosed in Wu et al, Proc Natl Acad Sci USA 2017, 3 months 28, 114(13) E2563-E2570.
In a further embodiment, the PPAR δ agonist compound is (R) -3-methyl-6- (2- ((5-methyl-2- (4- (trifluoromethyl) phenyl) -1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid or (R) -3-methyl-6- (2- ((5-methyl-2- (6- (trifluoromethyl) pyridin-3-yl) -1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid, or a pharmaceutically acceptable salt thereof.
In a further embodiment, the PPAR δ agonist compound is (R) -3-methyl-6- (2- ((5-methyl-2- (4- (trifluoromethyl) phenyl) -1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the PPAR δ agonist compound is the hemisulfate salt of (R) -3-methyl-6- (2- ((5-methyl-2- (4- (trifluoromethyl) phenyl) -1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid. In some embodiments, the PPAR δ agonist compound is a meglumine salt of (R) -3-methyl-6- (2- ((5-methyl-2- (4- (trifluoromethyl) phenyl) -1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid.
In a further embodiment, the PPAR δ agonist compound is (R) -3-methyl-6- (2- ((5-methyl-2- (6- (trifluoromethyl) pyridin-3-yl) -1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the PPAR δ agonist compound is the hemisulfate salt of (R) -3-methyl-6- (2- ((5-methyl-2- (6- (trifluoromethyl) pyridin-3-yl) -1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid. In some embodiments, the PPAR δ agonist compound is a meglumine salt of (R) -3-methyl-6- (2- ((5-methyl-2- (6- (trifluoromethyl) pyridin-3-yl) -1H-imidazol-1-yl) methyl) phenoxy) hexanoic acid.
In a further embodiment, the PPAR δ agonist compound is 2- (2-methyl-4- (((2- (4- (trifluoromethyl) phenyl) -2H-1,2, 3-triazol-4-yl) methyl) thio) phenoxy) acetic acid or a pharmaceutically acceptable salt thereof.
In a further embodiment, the PPAR δ agonist compound is (R) -2- (4- ((2-ethoxy-3- (4- (trifluoromethyl) phenoxy) propyl) thio) phenoxy) acetic acid or a pharmaceutically acceptable salt thereof.
The term "pharmaceutically acceptable salt" with respect to a PPAR δ agonist compound refers to a salt of a PPAR δ agonist compound that does not cause significant irritation to a mammal to which it is administered and does not substantially abrogate the biological activity and properties of the compound. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002.S.M.Berge, L.D.Bighley, D.C.Monkhouse, J.Pharm.Sci.1977,66,1-19.P.H.Stahl and C.G.Wermuth eds, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Surich: Wiley-VCH/VHCA, 2002. In some embodiments, pharmaceutically acceptable salts are generally more soluble and dissolve faster than non-ionic substances in gastric and intestinal fluids, and thus are useful in solid dosage forms. Furthermore, because their solubility is generally a function of pH, selective dissolution is possible in one or another portion of the digestive tract, and in some cases this ability is manipulated as an aspect of delayed and sustained release behavior. Furthermore, since the salt-forming molecule is in equilibrium with the neutral form in some cases, the pathway through the biological membrane is regulated in some cases.
In some embodiments, the pharmaceutically acceptable salt is typically prepared by reacting the free base with a pharmaceutically acceptable acidWith a suitable organic or inorganic acid or by reacting an acid with a suitable organic or inorganic base. The term may be used to refer to any compound of the invention. Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, propionate laurylsulfate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolylaminobenzarsonate, hexylisophthalate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, naphthalenesulfonate, nitrate, N-methylglucamine, Oxalate, pamoate (abrate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, theachlorate, tosylate, triethyliodide (triethiodode), trimethylammonium, and valerate. In some embodiments, when an acidic substituent is present, such as-CO2H, ammonium, morpholinium, sodium, potassium, barium, or calcium salts are formed. In some embodiments, when a basic group, such as an amino group or a basic heteroaromatic ring, such as pyridyl, is present, acid addition salts are formed, such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartrate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate, ethanesulfonate, picrate, and the like. Other pharmaceutically acceptable salt forms of therapeutic agents are listed in Berge et al, Journal of Pharmaceutical Sciences, Vol.66 (1), pp.1-19 (1977).
Certain terms
The following terms used in the present application have the definitions given below, unless otherwise specified. The use of the term "including" as well as other forms is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that there is no lasting deleterious effect on the overall health of the subject being treated.
As used herein, the term "modulate" refers to interacting directly or indirectly with a target to alter the activity of the target, including by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or extending the activity of the target.
As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions of agonists, partial agonists, inverse agonists, antagonists, degradants, or combinations thereof. In some embodiments, the modulator is an antagonist. In some embodiments, the modulator is a degrading agent.
As used herein, the term "administering" and similar words refer to a method that is capable of delivering a compound or composition to a desired biological site of action in some circumstances. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
As used herein, the term "co-administration" or the like is intended to include the administration of a selected therapeutic agent to a single patient, and is intended to include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.
As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an agent or compound administered that will alleviate to some extent one or more symptoms of the disease or condition being treated. The results include reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. In any individual case, an appropriate "effective" amount is optionally determined using techniques such as dose escalation studies.
As used herein, the term "enhance" refers to increasing or prolonging the efficacy or duration of a desired effect. Thus, with respect to enhancing the effect of a therapeutic agent, the term "enhance" refers to the ability to increase or prolong the effect of other therapeutic agents on the system in terms of efficacy or duration. As used herein, "enhancing effective amount" refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.
As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combination of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of the active ingredients, e.g., both a compound described herein or a pharmaceutically acceptable salt thereof and a co-agent, to a patient in the form of a single entity or dose. The term "non-fixed combination" refers to the administration of an active ingredient, e.g., a compound described herein or a pharmaceutically acceptable salt thereof, and a co-agent as separate entities either simultaneously, concurrently or sequentially (without specific intervening time limits) to a patient, wherein such administration provides effective levels of both compounds in the patient. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.
The terms "kit" and "article of manufacture" are used as synonyms.
The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. In one aspect, the mammal is a human.
As used herein, the term "treating" includes alleviating, or ameliorating at least one symptom of a disease or condition, preventing an additional symptom, inhibiting a disease or condition, e.g., arresting the development of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or stopping the symptoms of a disease or condition prophylactically and/or therapeutically.
Pharmaceutical composition
In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in conventional manner using one or more pharmaceutically acceptable inactive ingredients which facilitate processing of the active compounds into pharmaceutical preparations. Suitable formulations depend on the route of administration chosen. For example, an overview of The pharmaceutical compositions described herein can be found in Remington: The Science and Practice of Pharmacy, 19 th edition (Easton, Pa.: Mack Publishing Company, 1995); hoover, John e., Remington's Pharmaceutical Sciences, Mack Publishing co, Easton, Pennsylvania 1975; liberman, h.a. and Lachman, l. eds, Pharmaceutical document Forms, Marcel Decker, New York, n.y., 1980; and Pharmaceutical document Forms and Drug Delivery Systems, 7 th edition (Lippincott Williams & Wilkins1999), the disclosure of which is incorporated herein by reference.
In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition. Administration of the compounds and compositions described herein can be by any method that is capable of delivering the compound to the site of action. These methods include, but are not limited to, delivery via enteral routes (including oral, gastric or duodenal feeding tubes, rectal suppositories, and rectal enemas), parenteral routes (injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including epidermal, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although in some cases the most suitable route depends on, for example, the condition and disorder of the recipient. By way of example only, in some cases, the compounds described herein are administered topically to an area in need of treatment, such as by local infusion during surgery, by local application, such as a cream or ointment, by injection, by catheter, or by implant. In some cases, administration is by direct injection to the site of the diseased tissue or organ.
In some embodiments, the PPAR δ agonist compound is contained in a pharmaceutical composition. As used herein, the term "pharmaceutical composition" refers to a liquid or solid composition comprising a pharmaceutically active ingredient (e.g., a PPAR δ agonist compound) and at least one carrier, wherein no ingredient is generally biologically undesirable in the amounts administered.
The pharmaceutical compositions incorporating the PPAR δ agonist compounds take any physical form that is pharmaceutically acceptable. In some embodiments, the pharmaceutical compositions described herein are in a suitable form for oral administration. In one embodiment of such pharmaceutical compositions, a therapeutically effective amount of a PPAR δ agonist compound is incorporated.
In some embodiments, conventional inert ingredients and means of formulating pharmaceutical compositions are used. In some embodiments, known methods of formulating pharmaceutical compositions are followed. All common types of compositions are contemplated, including but not limited to tablets, chewable tablets, capsules, and solutions. However, the amount of PPAR δ agonist compound is best defined as the effective amount, i.e. the amount that provides the desired dosage of PPAR δ agonist compound to a subject in need of such treatment. In some embodiments, the activity of the PPAR δ agonist compounds is not dependent on the nature of the composition, and thus the composition is selected and formulated only for convenience and economy. Any of the PPAR δ agonist compounds described herein are formulated into a composition in any desired form.
In some cases, the capsules are prepared by mixing the PPAR δ agonist compound with a suitable diluent and filling the appropriate amount of the mixture in the capsules. Typical diluents include inert powdered substances such as many different kinds of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, cereal flour and similar edible powders.
In some cases, tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations typically incorporate diluents, binders, lubricants and disintegrants, as well as PPAR δ agonist compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars (such as lactose, fructose, glucose, etc.). Natural and synthetic gums are also convenient, including gum arabic, alginates, methylcellulose, polyvinylpyrrolidine, and the like. In some cases, polyethylene glycol, ethyl cellulose, and waxes are used as binders.
In some cases, the lubricant in the tablet formulation helps to prevent the tablet and punch from sticking in the die. In some cases, the lubricant is selected from solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils.
Tablet disintegrants are substances that swell when wetted to break up the tablet and release the compound. They include starch, clay, cellulose, orienters (align) and gums. More specifically, tablet disintegrants include corn and potato starch, methyl cellulose, agar, bentonite, wood cellulose, powdered natural sponges, cation exchange resins, alginic acid, guar gum, citrus pulp, carboxymethyl cellulose, and sodium lauryl sulfate.
Enteric formulations are commonly used to protect the active ingredient from the strongly acidic contents of the stomach. Such formulations are produced by coating a solid dosage form with a polymeric film that is insoluble in an acidic environment and soluble in an alkaline environment. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate.
Tablets are commonly used as sugar coatings for flavors and sealants. In some cases, PPAR δ agonist compounds are formulated into chewable tablets by using large amounts of a pleasant-tasting substance such as mannitol in the formulation.
In some cases, transdermal patches are used to deliver PPAR δ agonist compounds. Typically, patches contain a resin composition in which the active compound will dissolve or partially dissolve and remain in contact with the skin through a film that protects the composition. Other more complex patch compositions may also be used, particularly those having a membrane that is perforated with an infinite number of holes through which the drug is pumped by osmosis.
In any embodiment wherein a PPAR δ agonist compound is included in the pharmaceutical composition, such pharmaceutical composition is in some cases in a form suitable for oral use, for example as a tablet, troche, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, syrup or elixir. In some cases, compositions intended for oral use are prepared according to any known method, and in some cases, such compositions include one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. In some cases, tablets contain the active ingredient in admixture with pharmaceutically acceptable, non-toxic excipients which are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. In some cases, the tablets are uncoated or, in some cases, they are coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, in some cases, a time delay material such as glyceryl monostearate or glyceryl distearate is employed.
Methods of administration and treatment regimens
In one embodiment, a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is used in the manufacture of a medicament for treating a primary mitochondrial myopathy in a mammal. A method for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administering to the mammal a pharmaceutical composition comprising a therapeutically effective amount of a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof), an active metabolite, a prodrug.
In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and/or therapeutic treatment. In certain therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one symptom of the disease or condition. Effective amounts for such use will depend on the severity and course of the disease or condition, previous therapy, the patient's health, weight and response to the drug, and the judgment of the treating physician. A therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and/or dose ranging clinical trials.
In prophylactic applications, compositions containing PPAR δ agonist compounds (e.g., compound 1 or a pharmaceutically acceptable salt thereof) are administered to a patient susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose". In such use, the exact amount will also depend on the health, weight, etc. of the patient. When used in a patient, an effective amount for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health and response to the drug, and the judgment of the treating physician. In one aspect, prophylactic treatment includes administering to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a PPAR δ agonist compound (e.g., compound 1, or a pharmaceutically acceptable salt thereof) to prevent recurrence of symptoms of the disease or condition.
In certain embodiments, wherein the condition of the patient is not improved, administration of a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered chronically, i.e., for an extended period of time, including throughout the life of the patient, to improve or otherwise control or limit the symptoms of the disease or condition in the patient, as judged by the physician.
In certain embodiments in which the patient's condition is improved, the dose of drug administered is temporarily reduced or temporarily suspended for a period of time (i.e., a "drug holiday"). In particular embodiments, the length of the drug holiday is between about 2 days and about 1 year, including by way of example about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, about 12 days, about 15 days, about 20 days, about 28 days, or more than about 28 days. By way of example, the dose reduction during a drug holiday is about 10% -100%, including by way of example about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%.
Once the patient's condition has improved, a maintenance dose is administered as needed. Subsequently, in particular embodiments, the dosage or frequency of administration, or both, is reduced to a level that maintains an improved disease, disorder, or condition, depending on the symptoms. However, in certain embodiments, the patient requires chronic intermittent treatment when any symptoms recur.
In one aspect, a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered daily to a human with FAOD in need of treatment with the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered once daily. In some embodiments, the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered twice daily. In some embodiments, the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered three times daily. In some embodiments, the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered once every other day. In some embodiments, the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered twice per week.
In some cases, a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered once daily, twice daily, three times daily, or more times daily. In some cases, a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered twice daily. In some embodiments, the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered daily, every other day, 5 days weekly, every other week, two weeks monthly, three weeks monthly, twice monthly, three times monthly, or more frequently. In some embodiments, the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered twice daily, e.g., in the morning and in the evening. In some embodiments, the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, 4 years, 5 years, 10 years, or more. In some embodiments, the PPAR δ agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered twice daily for at least or about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more. In some embodiments, the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered once daily, twice daily, three times daily, four times daily, or more than four times daily for at least or about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more.
Typically, the dosage of a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) for use in the treatment of a disease or condition described herein in a human is often in the range of from about 0.1mg/kg body weight to about 10mg/kg body weight per dose. In one embodiment, the required dose is conveniently provided in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day. In some embodiments, the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is conveniently provided in divided doses that are administered simultaneously (or over a short period of time) once daily. In some embodiments, the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is conveniently provided in divided doses administered in twice daily aliquots.
In some embodiments, a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered orally to a human at a dose of about 0.1mg to about 10mg per kg body weight per dose. In some embodiments, the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered to the human in a continuous dosing schedule. In some embodiments, the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered to the human on a continuous daily dosing schedule.
The term "continuous dosing schedule" refers to the administration of a particular therapeutic agent at regular intervals. In some embodiments, a continuous dosing schedule refers to administration of a particular therapeutic agent at regular intervals without any drug holidays from the particular therapeutic agent. In some other embodiments, a continuous dosing schedule refers to administration of a particular therapeutic agent in a cyclical manner. In some other embodiments, a continuous dosing schedule refers to administration of a particular therapeutic agent in a drug administration cycle, followed by a drug holiday from the particular therapeutic agent (e.g., a washout period or other such period of time in which no drug is administered). For example, in some embodiments, a therapeutic agent is administered once daily, twice daily, three times daily, once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, seven times weekly, every other day, every three days, every four days, daily for a week, followed by a week without administration of the therapeutic agent; daily administration for two weeks followed by one or two weeks without administration of the therapeutic agent; daily administration for three weeks followed by one, two or three weeks without administration of the therapeutic agent; daily administration for four weeks followed by one, two, three, or four weeks without administration of a therapeutic agent; weekly, followed by one week without therapeutic administration; or every two weeks without the therapeutic agent subsequently. In some cases, the daily administration is once daily. In some cases, the daily administration is twice daily. In some cases, the daily administration is three times daily. In some cases, daily administration is more than three times daily.
The term "continuous daily dosing schedule" refers to the administration of a particular therapeutic agent daily at approximately the same time each day. In some cases, the daily administration is once daily. In some cases, the daily administration is twice daily. In some cases, the daily administration is three times daily. In some cases, daily administration is more than three times daily.
In some embodiments, the amount of PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered once daily. In some other embodiments, the amount of PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered twice daily. In some other embodiments, the amount of PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered three times daily.
In certain embodiments, wherein no improvement in the disease or condition state is observed in the human, the daily dose of the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is increased. In some embodiments, the once daily dosing schedule is changed to a twice daily dosing schedule. In some embodiments, a three times daily dosing schedule is employed to increase the amount of PPAR δ agonist compound (e.g., compound 1, or a pharmaceutically acceptable salt thereof) administered. In some embodiments, the frequency of administration by inhalation is increased to provide repeated high Cmax levels on a more regular basis. In some embodiments, the frequency of administration is increased to provide a maintained or more regular PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) exposure. In some embodiments, the frequency of administration is increased to provide repeated high Cmax levels on a more regular basis and to provide sustained or more regular PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) exposure.
In any of the preceding aspects are further embodiments that include a single administration of an effective amount of a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof), including the following further embodiments: wherein the PPAR δ agonist compound (i) is administered once daily; or (ii) multiple administrations over a time of day.
In any of the preceding aspects are further embodiments comprising multiple administrations of an effective amount of a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof), including the following further embodiments: wherein (i) the PPAR δ agonist compound is administered continuously or intermittently in a single dose; (ii) the time between administrations is every 6 hours; (iii) administering a PPAR δ agonist compound to the mammal every 8 hours; (iv) administering a PPAR δ agonist compound to the mammal every 12 hours; (v) the PPAR δ agonist compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday wherein the administration of the PPAR δ agonist compound is temporarily suspended, or the dose of the PPAR δ agonist compound administered is temporarily reduced; at the end of the drug holiday, administration of the PPAR δ agonist resumed. In one embodiment, the length of the drug holiday varies from 2 days to1 year.
Generally, a suitable dosage of a PPAR delta agonist compound, or a pharmaceutically acceptable salt thereof, for administration to a human will be between about 0.1mg/kg daily to about 25mg/kg daily (e.g., about 0.2mg/kg daily, about 0.3mg/kg daily, about 0.4mg/kg daily, about 0.5mg/kg daily, about 0.6mg/kg daily, about 0.7mg/kg daily, about 0.8mg/kg daily, about 0.9mg/kg daily, about 1mg/kg daily, about 2mg/kg daily, about 3mg/kg daily, about 4mg/kg daily, about 5mg/kg daily, about 6mg/kg daily, about 7mg/kg daily, about 8mg/kg daily, about 9mg/kg daily, about 10mg/kg daily, about 15mg/kg, about 20mg/kg daily, or about 25mg/kg per day). Alternatively, a suitable dose of a PPAR δ agonist compound or a pharmaceutically acceptable salt thereof for administration to a human will be from about 0.1 mg/day to about 1000 mg/day; about 1 mg/day to about 400 mg/day; or from about 1 mg/day to about 300 mg/day. In other embodiments, suitable dosages for a PPAR delta agonist compound or a pharmaceutically acceptable salt thereof for administration to a human will be about 1 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45 mg/day, about 50 mg/day, about 55 mg/day, about 60 mg/day, about 65 mg/day, about 70 mg/day, about 75 mg/day, about 80 mg/day, about 85 mg/day, about 90 mg/day, about 95 mg/day, about, About 100 mg/day, about 125 mg/day, about 150 mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, about 250 mg/day, about 275 mg/day, about 300 mg/day, about 325 mg/day, about 350 mg/day, about 375 mg/day, about 400 mg/day, about 425 mg/day, about 450 mg/day, about 475 mg/day, or about 500 mg/day. In some embodiments, the dose is administered more than once per day (e.g., two, three, four, or more times per day). In one embodiment, a suitable dose of a PPAR δ agonist compound or a pharmaceutically acceptable salt thereof for administration to a human is about 100mg twice daily (i.e., about 200 mg/day total). In another embodiment, a suitable dose of a PPAR δ agonist compound or a pharmaceutically acceptable salt thereof for administration to a human is about 50mg twice daily (i.e., about 100 mg/day total).
In some embodiments, a suitable dose of compound 1, or a pharmaceutically acceptable salt thereof, for administration to a human with a primary mitochondrial myopathy will be about 10 mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45 mg/day, about 50 mg/day, about 55 mg/day, about 60 mg/day, about 65 mg/day, about 70 mg/day, about 75 mg/day, about 80 mg/day, about 85 mg/day, about 90 mg/day, about 95 mg/day, about 100 mg/day, about 125 mg/day, about 150 mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, about 250 mg/day, about 275 mg/day, about 300 mg/day, about, About 325 mg/day, about 350 mg/day, about 375 mg/day, about 400 mg/day, about 425 mg/day, about 450 mg/day, about 475 mg/day, or about 500 mg/day. In some embodiments, a suitable dose of compound 1, or a pharmaceutically acceptable salt thereof, for administration to a human will be about 50 mg/day, about 100 mg/day, about 150 mg/day, about 200 mg/day, about 250 mg/day, about 300 mg/day, about 350 mg/day, about 400 mg/day, about 450 mg/day, or about 500 mg/day. In some embodiments, a suitable dose of compound 1, or a pharmaceutically acceptable salt thereof, for administration to a human will be about 50 mg/day. In some embodiments, a suitable dose of compound 1, or a pharmaceutically acceptable salt thereof, for administration to a human will be about 100 mg/day. In some embodiments, the dose is administered more than once per day (e.g., two, three, four, or more times per day).
In some embodiments, the amount of active in a daily dose or dosage form is below or above the ranges shown herein, based on a number of variables relating to the individual treatment regimen. In various embodiments, the daily dose and unit dose will vary according to a number of variables, including but not limited to the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition to be treated, the identity (e.g., body weight) of the human and the particular additional therapeutic agent administered (if applicable), and the judgment of the practitioner.
Toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, LD50And ED50And (4) determining. Dose ratio of toxic to therapeutic effects is therapeutic index, using LD50With ED50Is expressed by the ratio of (A) to (B). In certain embodiments, data obtained from cell culture assays and animal studies is used to formulate a therapeutically effective daily dosage range and/or therapeutically effective unit dose for mammals, including humans. In some embodiments, the daily dose of PPAR δ agonist compounds is at a dose that includes ED with minimal toxicity50In the circulating concentration range of (c). In certain embodiments, the daily dosage range and/or unit dose varies within this range, depending on the dosage form employed and the route of administration employed.
In some embodiments, no adverse effects are observed at a level (NOAEL) of at least 1, 10, 20, 50, 100, 500, or 1000mg (mpk) PPAR δ agonist compound per kilogram body weight after administration of a therapeutically effective dose of the PPAR δ agonist compound to the subject. In some examples, the NOAEL at 7 days for rats administered a PPAR δ agonist is at least about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, or 2000 mpk. In some examples, the NOAEL at 7 days for dogs administered a PPAR δ agonist compound is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500 mpk.
In some embodiments, Diagnosis of primary Mitochondrial myopathy in a mammal is confirmed by tissue biopsy and molecular genetic testing (e.g., Parikh S et al, Diagnosis and management of mitochondral disease: a consensus medical society. Gene. Med. 2015; 17(9): 689-701. doi:10.1038/gim. 2014.177).
Databases of human mitochondrial genomes are known, see e.g. MITOMAP, polymorphisms and mutation schemas in human mitochondrial DNA. See also, revised cambridge reference sequence (rCRS) for human mitochondrial DNA.
Tissue biopsy involves the study of a small sample of infected tissue under a microscope. In some embodiments, chemical tests performed on the tissue sample are also performed.
In some embodiments, the tissue biopsy comprises a muscle biopsy. In some embodiments, the tissue is subjected to various histological, biochemical and genetic studies. Tissue detection allows, but is not limited to, detection of mtDNA mutations with tissue specificity or low level heterogeneity and quantification of mtDNA content (copy number).
In some embodiments, the muscle histology includes, but is not limited to, hematoxylin and eosin (H & E), Gomori trichrome staining (for broken red fibers), SDH (for SDH-rich or broken blue fibers), NADH-TR (NADH-tetrazole reductase), COX (for COX negative fibers), and combined SDH/COX staining (COX intermediate fibers). Electron Microscopy (EM) examines mitochondrial content and ultrastructural abnormalities.
In some embodiments, functional in vitro assays are performed in tissues (typically muscle) to measure mitochondrial function. These tests assess various functions of the mitochondrial ETC or respiratory chain. Functional assays include enzymatic activity of individual components of the ETC, measurement of component activity, blue native gel electrophoresis, measurement of the presence of various protein components in complexes and super-complexes (achieved by western blotting and gel electrophoresis), and oxygen consumption using various substrates and inhibitors.
In some embodiments, the methods of treating primary mitochondrial myopathy in a mammal with a PPAR δ agonist compound described herein (e.g., compound 1 or a pharmaceutically acceptable salt thereof) result in an improvement in muscle histology, an increase in mitochondrial DNA copy number, an improvement in the level of heterogeneity, an improvement (e.g., an increase) in respiratory chain enzyme activity (e.g., without limitation, ATP-ADP level, fatty acid oxidation gene expression or flux), and an increase in mRNA levels (e.g., as measured using transcriptomics).
In some embodiments, the method of treating a primary mitochondrial myopathy in a mammal with a PPAR δ agonist compound described herein (e.g., compound 1 or a pharmaceutically acceptable salt thereof) results in an improvement in histology of a biopsy muscle sample taken from a mammal having the primary mitochondrial myopathy. In some embodiments, the histological improvement of the biopsy muscle sample comprises increasing mitochondrial mass. In some embodiments, the histological improvement of the biopsy muscle sample comprises a reduction in broken red fibers.
In some embodiments, the histological improvement of the biopsy muscle sample is improved by at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or greater than 95%.
In some embodiments, the mitochondrial DNA copy number is increased by at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or greater than 95%. In some embodiments, administration of a PPAR δ agonist compound described herein (e.g., compound 1 or a pharmaceutically acceptable salt thereof) to a mammal with a primary mitochondrial myopathy results in at least or about a 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or greater than 10-fold increase in mitochondrial DNA copy number.
In some embodiments, the level of heterogeneity is improved by at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or greater than 95%. In some embodiments, administration of a PPAR δ agonist compound described herein (e.g., compound 1 or a pharmaceutically acceptable salt thereof) to a mammal having a primary mitochondrial myopathy results in at least or about a 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or greater than 10-fold improvement in the level of heterogeneity.
In some embodiments, respiratory chain enzyme activity is increased by at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or greater than 95%. In some embodiments, administration of a PPAR δ agonist compound described herein (e.g., compound 1 or a pharmaceutically acceptable salt thereof) to a mammal with a primary mitochondrial myopathy results in at least or about a 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or greater than 10-fold increase in respiratory chain enzyme.
In some embodiments, the improvement is compared to a control. In some embodiments, the control is an individual who does not receive a PPAR δ agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, the control is an individual who does not receive a full dose of a PPAR δ agonist (e.g., compound 1, or a pharmaceutically acceptable salt thereof). In some embodiments, the control is a baseline of the subject prior to receiving the PPAR δ agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof).
In some embodiments, the method of treating primary mitochondrial myopathy in a mammal with a peroxisome proliferator-activated receptor delta (PPAR δ) agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) described herein results in an improvement in one or more outcome measures. In some embodiments, outcome measures include, but are not limited to, Patient Reported Outcomes (PRO),Exercise tolerance, systemic fatty acid oxidation (e.g.13CO2Production), blood acylcarnitine profile and blood inflammatory cytokines. In some embodiments, the baseline assessment is typically determined prior to administration of the PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof). The improvement in the outcome measure is assessed by repeated assessments made during treatment with PPAR δ agonist compounds and comparison to a baseline assessment and/or any previous assessment.
In some embodiments, one or more outcome measures are improved by at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or greater than 95%. In some embodiments, administration of a PPAR δ agonist compound described herein (e.g., compound 1 or a pharmaceutically acceptable salt thereof) to a mammal having a primary mitochondrial myopathy results in at least or about a 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or greater than 10-fold improvement in one or more outcome measures.
In some embodiments, the Patient Reported Outcome (PRO) is measured with a questionnaire. In some embodiments, the questionnaire encompasses health concepts related to the condition being treated. In some embodiments, the questionnaire encompasses health concepts related to the condition being treated, such as, but not limited to: physical function, physical pain, character limitation due to physical health issues, character limitation due to personal or emotional issues, emotional condition, social function, energy/fatigue, and overall health awareness, including awareness of health changes.
In some embodiments, the outcome measure is assessed by a test that assesses exercise tolerance or endurance. In some embodiments, exercise endurance is assessed by an exercise test. Exercise tests include, but are not limited to, sub-maximum treadmills, walk tests (e.g., 6 minutes; 12 minutes), run tests, treadmills, and ergometric exercise tests. In some embodiments, the exercise test is used in conjunction with a sensory exertion bogger scale. In some embodiments, the exercise test is performed according to guidelines set forth by the American Thoracic Society (ATS).
In some embodiments, treating the primary mitochondrial myopathy comprises increasing exercise tolerance, alleviating pain, reducing fatigue, increasing strength, increasing survival rate, or a combination thereof, in the mammal.
Treating primary mitochondrial myopathy in humans includes improving a human's perception of well-being, improving cognition, increasing exercise tolerance, alleviating pain, reducing fatigue, increasing strength, increasing survival rate, or a combination thereof.
In some embodiments, the improvement in health, pain, fatigue, and/or cognition in a human is determined by requiring the human receiving treatment to compare the above symptoms after treatment to before treatment.
In some embodiments, an improvement in a person's symptoms can be determined by requiring a caregiver to compare the subject's symptoms before and after treatment.
In some embodiments, improving exercise tolerance in a mammal comprises increasing endurance/exercise tolerance as measured by walking distance in a sit-stand test or a walk test (e.g., about a 6 minute walk test or a12 minute walk test). In some embodiments, the distance walked in such a walk test increases by at least about 1 meter, at least about 5 meters, at least about 10 meters, at least about 20 meters, at least about 30 meters, at least about 40 meters, at least about 50 meters, at least about 60 meters, at least about 70 meters, at least about 80 meters, at least about 90 meters, at least about 100 meters, or greater than about 100 meters.
As used herein, the term "about" means within ± 10% of the stated value.
In some embodiments, increasing exercise tolerance in the mammal comprises decreasing heart rate in a walking test for about 12 minutes. In some embodiments, the heart rate is decreased: 1 heartbeat per minute, 2 heartbeats per minute, 3 heartbeats per minute, 4 heartbeats per minute, 5 heartbeats per minute, at least about 10 heartbeats per minute, or at least about 20 heartbeats per minute.
In some embodiments, increasing exercise tolerance in a mammal comprises increasing the peak oxygen or maximum oxygen uptake (peak VO) of the mammal2Or VO2 max)。VO2max, also known as maximum oxygen uptake, is a measure of the maximum amount of oxygen one can utilize during strenuous exercise. It is a commonly used measure for determining the aerobic capacity of a person before or during exercise.
In some embodiments, peak VO2Expressed as absolute rates (e.g., liters of oxygen per minute (e.g., L/min)) or relative rates (e.g., milliliters of oxygen per kilogram of body weight per minute (e.g., mL/min/kg-min)).
In some embodiments, increasing exercise tolerance in a mammal comprises peak VO in the mammal2The measured increase is about 0.5mL/min/kg, about 1mL/min/kg, about 1.5mL/min/kg, about 2mL/min/kg, about 2.5mL/min/kg, about 3mL/min/kg, about 3.5mL/min/kg, about 4mL/min/kg, about 4.5mL/min/kg, about 5mL/min/kg, or greater than about 5 mL/min/kg.
In some embodiments, improving exercise tolerance in the mammal comprises decreasing the measured Respiratory Exchange Rate (RER).
In some embodiments, Respiratory Exchange Rate (RER) is measured to assess exercise tolerance. RER is carbon dioxide (CO) produced in metabolism2) Amount and oxygen (O) used2) The ratio of (a) to (b). In some embodiments, the ratio is determined by comparing exhaled air to room air.
In some embodiments, the pain of the mammal is assessed using the concise pain scale (BPI). BPI includes a questionnaire that assesses the severity of pain and the effect of pain on the daily function experienced. In some embodiments, the severity of pain is measured in tenths of a degree. In some embodiments, treating the primary mitochondrial myopathy with a PPAR δ agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) comprises a reduction in BPI score of 1,2,3, 4,5, or greater than 5.
In some embodiments, the level of fatigue or energy in the mammal is assessed using a Modified Fatigue Impact Scale (MFIS). Fatigue is a feeling of physical fatigue and lack of energy that many people experience from time to time. In some embodiments, a person with a medical condition such as primary mitochondrial myopathy experiences a more intense feeling of fatigue and greater impact more frequently than others. MFIS includes a questionnaire that assesses the effects of fatigue on a person's daily life. In some embodiments, the total MFIS score may range from 0 to 84. In some embodiments, treating the primary mitochondrial myopathy with a PPAR δ agonist (e.g., compound 1 or a pharmaceutically acceptable salt thereof) comprises a1, 2,3, 4,5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or greater than 20 reduction in MFIS score.
Combination therapy
In some cases, PPAR delta agonistsCompound (I)(e.g., Compound 1 or a pharmaceutically acceptable salt thereof) is suitably administered in combination with one or more other therapeutic agents.
In one embodiment, the PPAR δ agonist is a PPAR δ agonistCompound (I)(e.g., compound 1) or a pharmaceutically acceptable salt or solvate thereof, is enhanced by administration of an adjuvant (i.e., the therapeutic benefit of the adjuvant itself is less, but the overall therapeutic benefit to the patient is enhanced when combined with another therapeutic agent). Alternatively, in some embodiments, the benefit experienced by the patient is through administration of a PPAR δ agonistCompound (I)(e.g., compound 1) or a pharmaceutically acceptable salt or solvate thereof, and another agent that also has therapeutic benefit (which also includes a treatment regimen).
In a particular embodiment, the PPAR delta agonist isCompound (I)(e.g., Compound 1) or a pharmaceutically acceptable salt or solvate thereof, in combination with a second therapeutic agent, wherein the PPAR delta agonist isCompound (I)(e.g., compound 1), or a pharmaceutically acceptable salt or solvate thereof, and a second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing greater overall benefit than either therapeutic agent administered alone.
In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is a simple addition of the two therapeutic agents, or the patient experiences a synergistic benefit.
In certain embodiments, when PPAR delta agonistsCompound (I)(e.g., Compound 1) or a pharmaceutically acceptable salt or solvate thereof with one or more additional pharmaceutical agentsCompound (I)(e.g., additional therapeutically effective drugs, adjuvants, etc.) when administered in combination, various therapeutically effective doses of a PPAR δ agonist (e.g., compound 1), or a pharmaceutically acceptable salt or solvate thereof, will be used to formulate a pharmaceutical composition and/or for use in a therapeutic regimen. Therapeutically effective dosages of drugs and other agents used in the combination treatment regimen are optionally determined in a manner similar to that described above for the active per se. In addition, the prophylactic/therapeutic methods described herein include the use of metronomic dosing, i.e., providing more frequent low doses to minimize toxic side effects. In some embodiments, the combination treatment regimen comprises the following treatment regimens: wherein the PPAR delta agonistCompound (I)Administration of (e.g., compound 1), or a pharmaceutically acceptable salt or solvate thereof, begins before, during, or after treatment with the second agent described herein and continues until any time during or after the end of treatment with the second agent. Also included are treatments as follows: wherein the PPAR delta agonistCompound (I)(e.g., compound 1) or a pharmaceutically acceptable salt or solvate thereof and the second agent used in combination are administered simultaneously, or at different times, and/or at decreasing or increasing intervals during treatment. Combination therapy further includes periodic therapy that starts and ends at different times to aid in clinical management of the patient.
It will be appreciated that the dosage regimen for treating, preventing or ameliorating the condition to be alleviated will vary depending upon a number of factors, such as the disease, disorder or condition from which the subject is suffering, the age, weight, sex, diet and medical condition of the subject. Thus, in some instances, the dosage regimen actually employed is different from, and in some embodiments, departures from, the dosage regimen described herein.
For the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of co-drug employed, the particular drug employed, the disease or condition being treated, and the like. In other embodimentsIn embodiments, the PPAR delta agonist is administered in combination with one or more other therapeutic agentsCompound (I)(e.g., compound 1) or a pharmaceutically acceptable salt or solvate thereof, and one or more other therapeutic agents are administered simultaneously or sequentially.
In combination therapy, a plurality of therapeutic compounds, one of which is a PPAR δ agonist (e.g., compound 1) or a pharmaceutically acceptable salt or solvate thereof, are administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents are provided in a single, same form or in multiple forms (e.g., as a single pill or as two separate pills), by way of example only.
The PPAR δ agonist compound (e.g., compound 1), or a pharmaceutically acceptable salt or solvate thereof, and the combination therapy are administered before, during, or after the onset of the disease or condition, and the time of administration of the composition comprising the PPAR δ agonist compound (e.g., compound 1), or a pharmaceutically acceptable salt or solvate thereof, can vary. Thus, in one embodiment, compound I, or a pharmaceutically acceptable salt or solvate thereof, is used as a prophylactic medicament and is continuously administered to a subject predisposed to developing a condition or disease, in order to prevent the occurrence of the disease or condition. In another embodiment, the PPAR δ agonist compound (e.g., compound 1), or a pharmaceutically acceptable salt or solvate thereof, is administered during or as soon as possible after the onset of symptoms. In particular embodiments, a PPAR δ agonist compound (e.g., compound 1), or a pharmaceutically acceptable salt or solvate thereof, is administered as soon as feasible after the occurrence of a disease or condition is detected or suspected, and for the length of time required to treat the disease. In one embodiment, the length of time required for treatment is variable, and the length of treatment is adjusted to suit the particular needs of each subject. For example, in particular embodiments, a PPAR δ agonist compound (e.g., compound 1), or a pharmaceutically acceptable salt or solvate thereof, or a formulation containing compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered for at least 2 weeks, about 1 month to about 5 years。
Exemplary Agents for combination therapy
In some embodiments, a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with one or more additional therapies for treating primary mitochondrial myopathy.
In certain embodiments, at least one additional therapy is administered concurrently with the PPAR δ agonist compound (e.g., compound 1), or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the at least one additional therapy is administered less frequently than the PPAR δ agonist compound (e.g., compound 1) or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the at least one additional therapy is administered more frequently than the PPAR δ agonist compound (e.g., compound 1), or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the at least one additional therapy is administered prior to the administration of the PPAR δ agonist compound (e.g., compound 1), or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the at least one additional therapy is administered after administration of the PPAR δ agonist compound (e.g., compound 1), or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with panthenol, ubiquinone, niacin, riboflavin, creatine, L-carnitine, acetyl-L-carnitine, biotin, thiamine, pantothenic acid, pyridoxine, α -lipoic acid, N-heptanoic acid, CoQ10, vitamin E, vitamin C, methylcobalamin, folinic acid, resveratrol, N-acetyl-L-cysteine (NAC), zinc, folinic acid/calcium leucovorin, or a combination thereof.
In some embodiments, a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with panthenol, ubiquinone, niacin, riboflavin, creatine, L-carnitine, acetyl-L-carnitine, biotin, thiamine, pantothenic acid, pyridoxine, α -lipoic acid, N-heptanoic acid, CoQ10, vitamin E, vitamin C, methylcobalamin, folinic acid, N-acetyl-L-cysteine (NAC), zinc, folinic acid/leucovorin calcium, resveratrol, acipimox, elamipramitide, cysteamine, succinate, a NAD agonist, vatinone (EPI-743)), omavelloxolone (RTA-408), niacin, nicotinamide, elamipramitide, KL133, KH176, or a combination thereof.
In some embodiments, a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with succinic acid or a salt thereof, or trisuccinyl glycerol or a salt thereof. In some embodiments, a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a compound described in international PCT publication No. WO 2017/184583.
In some embodiments, the PPAR δ agonist compound (e.g., compound I or a pharmaceutically acceptable salt thereof) is administered in combination with an antioxidant.
In some embodiments, a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with an odd-chain fatty acid, an odd-chain fatty ketone, L-carnitine, or a combination thereof.
In some embodiments, a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered in combination with a triheptanoin, n-heptanoic acid, triglyceride, or salt thereof, or a combination thereof.
In some embodiments, the PPAR δ agonist compound is administered in combination with a nicotinamide adenine dinucleotide (NAD +) pathway modulator. NAD + plays a number of important roles within the cell, including acting as an oxidant in the oxidative phosphorylation of ATP generated from ADP. Increasing intracellular NAD + concentration will enhance the oxidative capacity within mitochondria, thereby increasing nutrient oxidation and promoting energy supply, which is the main role of mitochondria. In some embodiments, the NAD + modulator targets Poly ADP Ribose Polymerase (PARP), aminocarboxymuconate semialdehyde decarboxylase (ACMSD), and N' -nicotinamide methyltransferase (NNMT).
Kits and articles of manufacture
Described herein are kits for treating a primary mitochondrial myopathy in a subject comprising administering to the subject a PPAR δ agonist compound (e.g., compound 1, or a pharmaceutically acceptable salt thereof).
Kits and articles of manufacture are also described herein for use in the therapeutic applications described herein. In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers, such as vials, tubes, and the like, each container comprising one of the individual elements for the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In some embodiments, the container is formed from various materials, such as glass or plastic.
The articles provided herein comprise packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. Various formulations of the compounds and compositions provided herein are contemplated as various treatment modalities for any treatment of primary mitochondrial myopathy that would benefit from PPAR δ modulation.
The container optionally has a sterile access port (e.g., the container is an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise a compound and an identifying description or label or instructions relating to its use in the methods described herein.
A kit will typically include one or more additional containers, each container having one or more of the various materials (e.g., reagents, optionally in concentrated form, and/or devices) necessary for use of the compounds described herein from a commercial and user perspective. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; a carrier, a package, a container, a vial, and/or a tube label listing the contents and/or instructions for use, and a package insert with instructions for use. A set of instructions will also typically be included.
In some embodiments, the label is on or associated with the container. In some cases, the label is located on the container when the letters, numbers or other characters forming the label are attached, molded or etched into the container itself; in some cases, a label is associated with a container, for example as a package insert, when the label is present in a vessel or carrier that also holds the container. In some cases, the label is used to indicate the contents that will be used for a particular therapeutic application. In some cases, the label indicates instructions for use of the contents, e.g., in the methods described herein.
In certain embodiments, the pharmaceutical composition comprising a PPAR δ agonist compound (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is present in a package or dispenser device, which in some cases comprises one or more unit dosage forms. In some cases, the package comprises, for example, a metal or plastic foil, such as a blister pack. In some cases, the package or dispenser device is accompanied by instructions for administration. In some cases, the package or dispenser is further accompanied by a notice associated with the container in a format prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice reflects approval by the agency of the pharmaceutical form for human or veterinary administration. For example, in some cases, such a notification is a label approved by the U.S. food and drug administration for prescription drugs or an approved product insert. In some cases, compositions comprising a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in a suitable container, and labeled for treatment of a specified condition.
Examples
The following examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.
Example 1: cell lines and cultures
Subjects skin biopsies of fibroblast cultures were performed clinically with written informed consent from the subjects and/or legal guardians. Fibroblasts having a mutation of any one of the genes and/or proteins associated with primary mitochondrial myopathy are obtained from skin biopsies of patients, while wild-type (WT) fibroblasts are obtained from healthy individuals.
In some embodiments, the fibroblasts are obtained from a subject who has been confirmed to be diagnosed with a primary mitochondrial myopathy (e.g., an m.3243a > G mutation or an mtDNA mutation), or they may be purchased from commercial sources, for example, from the Coriell Institute for Medical Research (403Haddon Avenue, Camden, New Jersey 08103).
Cell culture and treatment cells were grown in Dulbecco's Modified Eagle Medium (DMEM) (Corning Life Sciences, Manassas, Va.) containing high glucose levels or in DMEM without glucose for 48-72 hours. Both media were supplemented with fetal bovine serum, glutamine, penicillin and/or streptomycin. In some experiments, fibroblasts were incubated with N-acetylcysteine, resveratrol, mitoQ, Trolox (a water-soluble analog of vitamin E), or bezafibrate prior to analyzing the parameters.
PPAR δ agonist compounds were dissolved in phosphate buffered saline PBS as stock solutions. When the culture reached about 85-90% confluence, an amount of compound was added directly to the cell culture medium in the flask as appropriate. The cultures were allowed to grow at 37 ℃ for 48 hours and then harvested. The harvested cell pellet was stored at-80 ℃ until immunoassay and enzyme assay analysis were performed. Samples of 1mL to 1.5mL of medium were also stored at-80 ℃ for acylcarnitines.
Example 2: measuring mitochondrial respiration
Oxygen Consumption Rate (OCR) was measured with a Seahorse XFe96 extracellular flow analyzer (Sea horse Bioscience, Billerica, MA).
Briefly, the device contains a fluorophore sensitive to changes in oxygen concentration that enables accurate measurement of cytochrome c oxidase (Complex IV) during OXPHOS-O2Reduction of the molecule to two H2The rate of O molecules. Cells were seeded at a density of 80,000 cells/well in growth medium in 96-well Seahorse tissue culture microplates. To ensure that the number of cells was the same, cells were seeded in Cell-Tak pre-coated Cell culture plates (BD Biosciences, San Jose, Calif.). All cell lines were measured in four to eight wells per cell line. Then, the whole set of experiments was repeated. Before running the Seahorse assay, in the absence of CO2The cells were incubated in unbuffered DMEM for 1 hour. Initial OCR is measured to establish a baseline (basal breath). 300nM of carbonyl cyanide 4- (trifluor) was also injectedMethoxy) phenylhydrazone (FCCP) (Seahorse XF cell mitochondrial pressure kit, Santa Clara, CA) maximum respiration was determined.
Example 3: ATP production assay
ATP production was determined by bioluminescence assay using the ATP assay kit from PerkinElmer Inc, Waltham, MA (ATPlite kit) according to the manufacturer's instructions.
Example 4: fatty Acid Oxidation (FAO) flux analysis
By quantifying the amount of 9,10-, [ from conjugated to fatty acid-free albumin in fibroblasts cultured in 24-well plates3H]Produced from palmitate (PerkinElmer, Waltham, MA)3H2O for Fatty Acid Oxidation (FAO) flux analysis.
A representative, non-limiting example of FAO flux analysis is described in Bennett, M.J.assays of failure acid beta-oxidation activity. methods Cell Biol 80, 179-197, (2007). In some embodiments, 300,000 fibroblasts are plated in each well of a 6-well plate and grown in DMEM with 10% fetal bovine serum for 24 hours. The growth medium was then changed to the same medium or to that medium without glucose and the fibroblasts were grown as described for 48 hours. Subsequently, the cells were washed once with PBS and then mixed at 37 ℃ with 0.34. mu. Ci [9,10-3H]Oleate (45.5 Ci/mmol; Perkin Elmer, Waltham, Mass.) was incubated for 2 hours. The fatty acids were dissolved with alpha-cyclodextrin as described (Watkins, p.a., Ferrell, e.v.jr., Pedersen, J.I.&Hoefler, G.Peroximatic failure acid beta-oxidation in HepG2 cells, Arch Biochem Biophys 289, 329-336 (1991)). After incubation, the released material was loaded onto a column containing 750. mu.L of anion exchange resin (AG 1X8, acetate, 100-200 Mesh, BioRad, Richmond, CA)3H2O is separated from the oleate. After the culture medium passed through the column, the plate was washed with 750 μ L of water, which was also transferred to the column. The resin was then washed twice with 750 μ L of water. All eluates were collected in scintillation vials and mixed with 5mL scintillation fluid (Eco-lite, MP) followed by tritiumCounting in a beckmann scintillation counter in a window. Quadruplicate assays were performed with triplicate blanks (cell-free wells). The standard contained 50 μ L aliquots of incubation mixture, as well as 2.75mL of deionized water and 5mL of scintillation fluid.
Example 5: western blot
Cells were grown in T175 flasks and harvested by trypsinization at 90-95% confluence, pelleted and stored at-80 ℃ for western blotting. Using DCTMProtein assay kits (Bio-Rad Laboratories) quantify protein content in samples for data normalization.
For cell lysates, the pellet was resuspended in 150-250 μ L RIPA buffer with protease inhibitor cocktail (Roche Diagnostics, Mannheim, Germany). The homogenate was kept on ice for 30 minutes, shaken every 10 minutes, and centrifuged. The supernatant was used for western blotting. For mitochondria, the pellet was resuspended in 150. mu.L of Tris buffer (pH 7.4) containing 250mM sucrose, 2mM EDTA, protease inhibitor cocktail (Roche Diagnostics, Mannheim, Germany) and 0.5. mu.M trichostatin A (Sigma-Aldrich Co., St. Louis, Mo.), homogenized and centrifuged. The pellet was discarded and the supernatant centrifuged. The resulting pellet containing mitochondria was resuspended in 50mM Tris buffer (pH 7.4), sonicated and centrifuged again.
As previously described, cell lysates or mitochondria are used in western blots as previously described (e.g., Goetzman, e.s. et al, mol. genet. metab.91,138-147, (2007)).
Example 6: immunofluorescence microscopy and mitochondrial membrane potential (immunofluorescence)
Cells were incubated with antibodies anti-VLCAD (1:1000), anti-Nrf 2(1:100), or anti-NF-kB (1:1000) overnight at 4 ℃. After a brief wash with TBST, cells were incubated with the donkey anti-rabbit secondary antibody Alexa Fluor 488 from Invitrogen. Nuclei were immunostained with DAPI. The coverslip was then mounted using mounting media, after which images were taken at 60 x magnification using an Olympus Confocal FluoroView1000 microscope.
Example 7: cell viabilityForce measurement
Cell viability was assessed using a 3- (4, 5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium (MTS) assay kit according to the manufacturer's instructions (Abcam, Cambridge, MA). The absorbance was read at 490nm in a FLUOstar Omega plate reader.
Example 8: apoptosis assay
Using AlexaThe 488 annexin V/dead cell apoptosis kit evaluates apoptosis according to the manufacturer's instructions (Invitrogen, Grand Island, NY). The kit contains annexin V labeled with a fluorophore and Propidium Iodide (PI). Annexin V can recognize apoptotic cells by binding to phosphatidylserine exposed on the outer leaves of the plasma membrane of the cell, while PI stains dead cells by binding to nucleic acids. Fluorescence was measured in a Becton Dickinson FACSAria II flow cytometer (BD Biosciences, San Jose, Calif.).
Example 9: determination of acylcarnitine levels
Acylcarnitine analyses were performed using an appropriate tandem mass spectrometry (MS/MS) protocol.
Example 10: in vivo gene expression assessment in mouse muscle
Male C57BL/6 mice were administered compound 1 once daily for 7 consecutive days at an oral dose of 30 mg/kg. All mice were euthanized 4 hours after the last dose on day 7, and two quadriceps muscle samples were excised from the left and right limbs. Compound 1 treatment altered the expression pattern of a number of well-known PPAR δ regulatory genes and pathways important for fatty acid transport to the mitochondria (CPT1b), oxidative phosphorylation (PDK4) and mitochondrial biogenesis (PGC-1 α).
In the second study, male C57BL/6 mice were dosed once daily for four consecutive days. On the first day of treatment, all mice in each group received a single dose of vehicle or 30mg/kg of compound 1. Five mice of each group were anesthetized and euthanized at each of the following time points after the first day of dosing: 1.2, 4, 8, 24, 48, 72 and 96 hours. Animals remaining after 24 hours at time point receive the second dose. Animals remaining after 48 hours at time point received a third dose. Animals remaining after 72 hours at time point receive the fourth dose. Mice designated for time point 96 hours were euthanized on day 5. At 48 hours, compound 1 treatment increased the expression of PGC1 α (the major regulator of mitochondrial biogenesis) and CPT1b (the rate controlling enzyme of the long chain fatty acid β -oxidation pathway in muscle mitochondria).
Example 11: combination therapy
In some embodiments, the PPAR δ agonist is used in combination with other therapies for Primary Mitochondrial Myopathy (PMM). In some embodiments, a PPAR δ agonist compound is administered to a subject having (PMM) in combination with one or more of: ubiquinol, ubiquinone, nicotinic acid, riboflavin, creatine, L-carnitine, acetyl-L-carnitine, biotin, thiamine, pantothenic acid, pyridoxine, alpha-lipoic acid, N-heptanoic acid, CoQ10, vitamin E, vitamin C, methylcobalamin, folinic acid, N-acetyl-L-cysteine (NAC), zinc, folinic acid/leucovorin calcium, resveratrol, acipimox, elamipramitide, cysteamine, succinate, NAD agonists, vatiquinone (EPI-743)), omaloxolone (RTA-408), nicotinic acid, nicotinamide, elamipramitide, KL133, and KH 176.
Combination therapy is advantageous when efficacy is greater than either agent alone or when the required dose of either drug is reduced, thereby improving the side effect profile.
Example 12: determination of binding Selectivity of Compound 1 to PPAR α, PPAR δ and PPAR δ
Compound 1 was tested for all three human PPAR subtypes (hPPAR): hPPAR α, hPPAR γ, and hPPAR δ. Representative experimental results for each human PPAR subtype are shown in table 1. All assays were repeated at least 3 times for each subtype. Compound 1 is a potent PPAR δ agonist (EC50 ═ 31nM), while this compound shows only minimal activity against PPAR α (EC50>10 μ M) and PPAR γ (EC50>10 μ M).
The target gene was synthesized and cloned into the appropriate Jump-In according to the user's guidelines for Jump-In TM T-RExTM HEK293 retargeting kit (ThermoFisher, Cat. No. A15008)TMRetargeting into the vector. For example, the vector would be used to transfect and retarget Jump-InTMHEK293 GripTiteTMA parental cell line. The stable pool will be antibiotic selected over a period of about 21 days and tested for target gene expression by functional assays.
The retargeting method comprises the following steps:
growth medium without antibiotics Jump-InTMGripTiteTMHEK293 parental cells were plated at 60-80% confluence in T-75 flasks and usedLTX (50. mu.L) and PLUSTMReagents (20. mu.L) were transfected with the expression construct and the R4 integrase expression construct at a 1:1 ratio (20. mu.g DNA total). After 48 hours of incubation, 600. mu.g/mL ofAnd 10. mu.g/mL blasticidin cells were selected in growth medium for about 21 days.
BLA measurement method:
mixing Jump-InTMGripTiteTMHEK293 rpra α, δ or γ UAS-bla-Gal4 cell pools were plated in a 384 well plate format (20,000 cells per well) in OptiMeM without FBS repeatedly (n-4). Cells were allowed to adhere for 8 hours before adding compound 1 (maximum concentration of 1mM, 3-fold dilution, 10-point titration). After 16 hours, cells were loadedIt is a fluorescent BLA substrate that gives blue/green readings of expressing/non-expressing cells, respectively. The blue/green readings were measured on a fluorescence plate reader (Tecan Safire II).
Example 13: clinical trials of Primary Mitochondrial Myopathy (PMM)
Non-limiting examples of clinical trials for human primary mitochondrial myopathy are described below.
Purpose(s) to: the purpose of this study was: assessing the safety and tolerability of 12 weeks of treatment of a subject with primary mitochondrial myopathy with compound 1 or a pharmaceutically acceptable salt or solvate thereof; studying the pharmacokinetics of compound 1 or a pharmaceutically acceptable salt or solvate thereof in a subject with primary mitochondrial myopathy treated with compound 1 or a pharmaceutically acceptable salt or solvate thereof; studying the pharmacodynamic effect of compound 1, or a pharmaceutically acceptable salt or solvate thereof, on a subject with primary mitochondrial myopathy treated with compound 1, or a pharmaceutically acceptable salt or solvate thereof.
And (3) intervention:administering to the patient 10-2000mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, as a single agent or in combination per day. For example, a subject receives 100mg of compound 1, or a pharmaceutically acceptable salt or solvate thereof, once daily for 12 weeks. Other groups are considered.
Compound 1 or a pharmaceutically acceptable salt or solvate thereof will be packaged as a capsule in a bottle.
Detailed description:compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered orally to a patient once daily.
Inclusion criteria were:primary Mitochondrial Myopathy (PMM) as defined by the international seminar act: outcome measures and clinical trial readiness for pediatric and Adult primary Mitochondrial myopathy (Mancuso, M. et al, (2017, Dec.) International seminar: outcome measures and clinical trial readiness for pediatric and Adult primary Mitochondrial myopathy. Consensus recordings.10-18 November2016, Rome, Italy. Neurousacul.Disord., 12, 1126. 1137), wherein the myopathy score ranged from 2 to 4 in New castle Mitochondrial Disease Adult Scale (NMDAS) part III, issue 5. About 12 subjects confirmed m.3243A>G mutation, and 12 subjects had other mtDNA defects with myopathy.
A stable diet regimen to avoid fasting is currently followed as evidenced by the 3-day diet record obtained during the screening period.
There was a stable treatment regimen for at least 30 days prior to group entry.
Stable diet and medical care was expected and desired throughout the study.
Can walk and can carry out research exercise test.
Sufficient renal function as defined by a glomerular filtration rate (eGFR) of ≧ 60mL/min/1.73m2 estimated using the Cockcroft-Gault equation.
Capsules can be taken.
Exclusion criteria: subjects presenting with any of the following will not be included in the study:
unstable or poorly controlled diseases, as determined by one or more of the following: echocardiography has evidence of active or worsening cardiomyopathy at screening; acute rhabdomyolysis symptoms exist, and the increase of serum CPK is consistent with acute exacerbation of myopathy; evidence of acute crisis from its underlying disease.
Anticoagulants are currently administered.
Motor abnormalities other than those associated with mitochondrial diseases with possible interference with outcome measures.
Treatment with study drug within 3 months prior to day 1.
-the investigator believes evidence of significant concomitant clinical disease that may require altered management during the study or that may interfere with the conduct or safety of the study. (for well-controlled stable chronic conditions such as controlled hypertension (BP <140/90mmHg) thyroid disease, well-controlled type 1 or type 2 diabetes (HbA1c < 8%), hypercholesterolemia, gastroesophageal reflux, or drug-controlled (except tricyclic antidepressants) depression, it is acceptable as long as symptoms and drugs are not expected to compromise safety or interfere with the testing and interpretation of this study).
-history of cancer other than skin cancer in situ.
Hospitalization (as confirmed by the primary investigator) for any major medical condition within 3 months prior to screening.
Clinically significant heart disease or ECG abnormalities.
Any condition that may reduce drug absorption (e.g., gastrectomy).
A history of clinically significant liver disease, as evidenced by elevations of ALT, GGT or TB.
Hepatitis B surface antigen (HBsAg) or hepatitis C or HIV positive at the time of screening.
Evidence of a clinically significant muscle injury test (CPK >3x ULN).
History of drug abuse or positive urine drug screening.
History of regular drinking more than 14 times per week (1 time 150mL wine or 360mL beer or 45mL spirit) within 6 months of screening.
-pregnant or lactating women.
History of sensitivity to PPAR agonists.
The investigator believes that any other serious acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study product administration or may interfere with interpretation of study results.
Primary outcome measure: the safety endpoints include: the number and severity of adverse events. Absolute values at week 12, occurrence of changes from baseline, and incidence of clinically significant changes in: testing the safety of a laboratory; an electrocardiogram; supine vital signs.
Pharmacokinetic endpoints include: compound 1 plasma concentration and metabolite identification using pooled plasma.
Absolute values and changes from baseline to week 12 for serum biomarkers: fibroblast growth factor 21(FGF-21) and growth/differentiation factor 15 (GDF-15). Absolute values and changes from baseline to week 12 in the acylcarnitine group. Change in muscle histopathology from baseline to week 12.
Change from baseline after 12 weeks of treatment with compound 1: peak motion tests (including Borg scale); sub-extreme exercise tests (including Borg scale); distance walked in the 12 minute walk test (including gait analysis); sit-stand for 30 seconds.
Change from baseline after 12 weeks of treatment with compound 1 in muscle biopsy biomarkers (ranked by importance if samples are rare): mitochondrial DNA copy number; level of heterogeneity, respiratory chain enzyme activity (ATP-ADP level, fatty acid oxidation gene expression or flux); messenger ribonucleic acid (mRNA) levels using transcriptomics; change from baseline in NMDAS; change from baseline in SF-36; correcting for changes in fatigue impact scale score from baseline; change from baseline on a concise pain scale (short form).
PMM clinical trial results Using Compound 1
In general, compound 1 was well tolerated in subjects participating in the study.
An improvement in exercise tolerance was observed in subjects receiving 100mg of compound 1, or a pharmaceutically acceptable salt or solvate thereof, once daily for 12 weeks. During the 12 minute walk test, the subject was able to increase the walking distance. Figure 1 shows the results of the effect of compound 1 on the 12-minute walk test in this group of subjects. In the same group of subjects, peak VO was observed for many subjects who received 100mg of compound 1 or a pharmaceutically acceptable salt or solvate thereof once a day for 12 weeks2The trend toward an increase.
A reduction in the concise pain index (BPI) was observed in subjects receiving 100mg of compound 1, or a pharmaceutically acceptable salt or solvate thereof, once daily for 12 weeks. Figure 2 shows the reduction in mean BPI score resulting from administration of compound 1, or a pharmaceutically acceptable salt or solvate thereof, to this group of subjects. In the same group of subjects, a trend of increasing the modified fatigue impact scale score was observed for many subjects receiving 100mg of compound 1, or a pharmaceutically acceptable salt or solvate thereof, once daily for 12 weeks.
The examples and embodiments described herein are for illustrative purposes only and various modifications or changes in light thereof suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.
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