NPRA agonists, compositions and uses thereof

文档序号：1642880 发布日期：2019-12-20 浏览：41次中文

阅读说明：本技术 Npra激动剂、组合物及其用途 (NPRA agonists, compositions and uses thereof ) 是由 G·M·卡斯蒂洛 A·尼希莫托-阿施菲尔德 E·波罗汀于 2018-03-21 设计创作，主要内容包括：本公开提供了式(I)的利尿钠肽衍生物和包含式(I)的利尿钠肽衍生物的组合物,(脂肪酰基)z-(B)x-(G)y-NP(I),其中：z为1,x为2至4的整数,和y为3；或z为0,x为0至4的整数,和y为1至3的整数；脂肪酰基包含12至24(例如,12至18)个碳原子；B为赖氨酸或精氨酸；G为甘氨酸；NP为利尿钠肽；如果存在,(脂肪酰基)z-共价连接到(B)x的N-端；(脂肪酰基)z-(B)x-共价连接到(G)y的N-端；(脂肪酰基)z-(B)x-(G)y-共价连接到NP的N-端。根据本公开的利尿钠肽衍生物及其组合物可用于疾病如高血压、血管充血和心脏病的治疗。(The present disclosure provides natriuretic peptide derivatives of formula (I) and compositions comprising natriuretic peptide derivatives of formula (I), (fatty acyl groups) z ‑(B) x ‑(G) y -np (i), wherein: z is 1, x is an integer from 2 to 4, and y is 3; or z is 0, x is an integer from 0 to 4, and y is an integer from 1 to 3; fatty acyl groups contain 12 to 24 (e.g., 12 to 18) carbon atoms; b is lysine or arginine; g is glycine; NP is natriuretic peptide; if present, (fatty acyl) z -covalently linked to (B) x The N-terminus of (1); (fatty acyl group) z ‑(B) x -covalent bondingIs connected to (G) y The N-terminus of (1); (fatty acyl group) z ‑(B) x ‑(G) y -covalently linked to the N-terminus of the NP. Natriuretic peptide derivatives and compositions thereof according to the present disclosure are useful for the treatment of diseases such as hypertension, vascular congestion, and heart disease.)

1. A composition comprising a natriuretic peptide derivative of formula (I),

(fatty acyl group)_z-(B)_x-(G)_y-NP

(I)，

Wherein:

z is 1, x is an integer from 2 to 4, and y is 3; or

z is 0, x is an integer from 0 to 4, and y is an integer from 1 to 3;

fatty acyl groups contain 12 to 24 (e.g., 12 to 18) carbon atoms;

b is lysine or arginine;

g is glycine;

NP is natriuretic peptide;

if present, (fatty acyl)_z-covalently linked to (B)_xThe N terminal of (1);

(fatty acyl group)_z-(B)_x-covalently linked to (G)_yThe N terminal of (1); and

(fatty acyl group)_z-(B)_x-(G)_y-covalently linked to the N-terminus of the NP.

2. The composition of claim 1, wherein the natriuretic peptide derivative increases the level of blood cGMP upon parenteral administration to a mammal to a level greater than the natriuretic peptide NP upon parenteral administration to a mammal at an equivalent dose (e.g., a molar/Kg dose, a mg/Kg dose, or both a molar/Kg and mg/Kg dose).

3. The composition of claim 1 or 2, wherein NP is selected from human ANP (sequence ID1), rodent ANP (sequence ID19), human BNP (sequence ID41) and human CNP (sequence ID 57).

4. The composition of any one of claims 1 to 3, wherein NP is human ANP (sequence ID 1).

5. The composition of any one of claims 1-3, wherein NP is rodent ANP (sequence ID 19).

6. The composition according to any one of claims 1 to 3, wherein NP is human BNP (sequence ID 41).

7. The composition of any one of claims 1 to 3, wherein NP is human CNP (sequence ID 57).

8. The composition of any one of claims 1 to 7, wherein B is lysine.

9. The composition of any one of claims 1 to 8, wherein the natriuretic peptide derivative has the formula (II)

Fatty acyl radical- (B)_x-(G)₃-NP

(II)，

Wherein:

the fatty acyl group contains 12 to 24 (e.g., 12 to 18) carbon atoms;

b is lysine or arginine;

x is an integer from 2 to 4;

g is glycine;

NP is natriuretic peptide;

fatty acyl-covalently attached to (B)_xThe N terminal of (1);

fatty acyl radical- (B)_x-covalently linked to (G)₃The N terminal of (1); and

fatty acyl radical- (B)_x-(G)₃-covalently linked to the N-terminus of the NP.

10. The composition of any one of claims 1 to 9, wherein x is 2.

11. The composition of any one of claims 1 to 9, wherein x is 3.

12. The composition of any one of claims 1 to 9, wherein x is 4.

13. The composition of any one of claims 1 to 12, wherein fatty acyl group comprises 18 carbon atoms.

14. The composition of any one of claims 3 to 13, wherein- (B)_x-(G)₃-is selected from the group consisting of-KKGGG-, -KKKGGG-and-KKKKGGG-.

15. The composition of any one of claims 3 to 14, wherein the natriuretic peptide derivative is as defined by one of sequence ID9, sequence ID10, sequence ID11, sequence ID 14, sequence ID 18, sequence ID 56, sequence ID 82, sequence ID 52, sequence ID 113, sequence ID68, sequence ID 122, and sequence ID 72.

16. The composition of any one of claims 3 to 14, said natriuretic peptide derivative being as defined by one of sequence ID9, sequence ID10, sequence ID11, sequence ID 14, sequence ID 18, sequence ID 56 and sequence ID 72.

17. The composition of any one of claims 3 to 14, said natriuretic peptide derivative being as defined by one of sequence ID 14, sequence ID 18, sequence ID 56, sequence ID 82, sequence ID 52, sequence ID68, sequence ID 122 and sequence ID 72.

18. The composition of any one of claims 3 to 14, wherein the natriuretic peptide derivative is as defined by one of sequence ID 73, sequence ID 74, sequence ID 79, sequence ID 80, sequence ID 81, sequence ID83, sequence ID 84, and sequence ID 85.

19. The composition of any one of claims 3 to 14, said natriuretic peptide derivative being as defined by one of sequence ID 93, sequence ID 94, sequence ID 95, sequence ID 102, sequence ID 103, sequence ID 104, sequence ID 111, sequence ID 112, sequence ID 113, sequence ID 120, sequence ID 121, and sequence ID 122.

20. The composition according to any one of claims 1 to 8, wherein the natriuretic peptide derivative is of formula (III),

(B)_x-(G)_y-NP

(III)，

wherein:

b is lysine or arginine;

x is an integer from 0 to 4;

g is glycine;

y is an integer of 1 to 3;

NP is natriuretic peptide; and

(B)_x-(G)_y-covalently linked to the N-terminus of the NP.

21. The composition of claim 20, wherein x is 0.

22. The composition of claim 20, wherein x is 1.

23. The composition of claim 20, wherein x is 2.

24. The composition of claim 20, wherein x is 3.

25. The composition of claim 20, wherein x is 4.

26. The composition of any one of claims 20 to 25, wherein y is 1.

27. The composition of any one of claims 20 to 25, wherein y is 2.

28. The composition of any one of claims 20 to 25, wherein y is 3.

29. The composition of claim 20, wherein (B)_x-(G)_y-is selected from the group consisting of G-, GG-, GGG-, KGGG-and KKKKGGG-.

30. The composition of any one of claims 20 to 29, wherein the natriuretic peptide derivative is as defined by one of sequence ID2, sequence ID 3, sequence ID4, sequence ID5, sequence ID8, and sequence ID 44.

31. The composition of any one of claims 1 to 30, further comprising an excipient.

32. A composition according to any one of claims 1 to 31 for use in the treatment of a disease.

33. The composition of claim 32, wherein the disease is selected from the group consisting of hypertension, vascular congestion, and heart disease.

34. The composition for use according to claim 33, wherein the disease is a heart disease.

35. The composition for use according to any one of claims 32 to 34, wherein the treatment of the disease comprises parenteral administration of the natriuretic peptide derivative to a patient at a dose of less than 1.5mg/Kg body weight per day.

36. A method of treating a disease in a patient, the method comprising parenterally administering to the patient a composition according to any one of claims 1 to 30.

37. A method of increasing the blood cGMP of a patient, the method comprising parenterally administering to the patient a composition according to any one of claims 1 to 30.

38. The method of claim 36 or claim 37, wherein the composition is administered to the patient at a dose of less than 1.5mg natriuretic peptide derivative per Kg body weight per day.

39. The method of claim 38, wherein the composition is administered to the patient at a dose of less than 0.3mg natriuretic peptide derivative/Kg body weight per day.

40. Use of a composition according to any one of claims 1 to 30 for the preparation of a medicament for the treatment of a disease.

41. The use of claim 40, wherein the disease is selected from the group consisting of hypertension, vascular congestion, and heart disease.

Background

Increasing cyclic guanosine monophosphate (cGMP) in vivo has many applications in various hypertension, vascular congestion, or heart disease in mammals. Attempts to increase cGMP in vivo to treat various cardiovascular diseases or enhance sexual ability have led to the use of phosphodiesterase (phosphodiesterase) inhibitors 5, 6 and 9 (phosphodiesterases are enzymes that break down cGMP) (see, e.g., KeravisT, Lugnier c.br J pharmacol.2012; 165: 1288-305) or compounds that increase cGMP production such as nitroglycerin/nitrate and natriuretic peptides.

Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) act through the natriuretic receptor a (npra), and c-type natriuretic peptide (CNP) act through the natriuretic receptor b (nprb) (see, e.g., Silver MA, curr. opin. nephrol. hypertens.,2006, vol.15, 14-21; Yoshibayashi m. et al, eur.j. endocrinol.,1996, vol.135,265-268) to increase intracellular cGMP, which is also reflected in some degree by an increase in blood cGMP. When a natriuretic receptor ligand binds to a natriuretic transmembrane receptor with an intracellular guanylate cyclase domain, guanylate cyclase activity is activated, resulting in an increase in intracellular cGMP, expression of various physiological activities, and an increase in blood cGMP.

An increase in cGMP has a beneficial effect on hypertension and/or vascular fluid congestion and/or heart disease. Intracellular cGMP is broadly referred to as an intracellular second messenger, which is responsible for mediating extracellular signals (from natriuretic peptides such as ANP, BNP, CNP, urodilantin, and nitrous oxide) into intracellular actions. This has been well tested in controlling vascular smooth muscle tone. It is well known that an increase in intracellular cGMP in vascular smooth muscle cells relaxes smooth muscle and lowers blood pressure.

ANP and BNP are known agents for controlling blood pressure and cardiac load in patients with heart disease. In japan, human anp (hanp) is clinically used as a therapeutic agent for acute heart failure, while in the united states, BNP is clinically used as a therapeutic agent for congestive heart failure. The medical use of existing natriuretic peptides is limited by their short half-life and limited activity to provide sufficient cGMP and are typically administered by continuous intravenous infusion.

ANP, BNP and CNP are peptides having a cyclic structure necessary for their activity, which is possible due to the presence of disulfide bonds. ANP is a 28 amino acid peptide produced in and secreted from atrial cells. The peptide exhibits diuretic action in the kidney and relaxes and dilates vascular smooth muscle in blood vessels. In addition, ANP antagonizes the actions of the renin-angiotensin-aldosterone system (RAAS) and vasopressin. These effects reduce the overall load on the heart by lowering blood pressure and body fluid volume. Indeed, in congestive heart failure and the like, secretion of ANP is promoted with an increase in atrial filling pressure, and ANP alleviates the symptoms of congestive heart failure via the above-described actions.

BNP is a 32 amino acid peptide that is first found in the brain, but later is found to be produced and secreted mainly in cardiac myocytes. The secretion of BNP is increased in a heart failure patient, and BNP alleviates various symptoms associated with heart failure via the above-described actions.

In addition to vasodilation and regulation of blood pressure and vascular fluid by diuresis, ANP and BNP also have a variety of physiological activities. For example, the effects of ANP on inflammation and associated endothelial barrier failure caused by bacterial infection have been reported (see, e.g., Xing j., et al, j.appl.physiol.,2011,110(1), 213-224).

There is a need for natriuretic peptides with enhanced half-life and activity. The present disclosure seeks to meet this need and provide further related advantages. For example, the present disclosure provides novel compositions having surprisingly enhanced activity as measured by an increase in cGMP.

Disclosure of Invention

The present disclosure provides natriuretic peptide derivatives of formula (I) or compositions comprising natriuretic peptide derivatives of formula (I):

(fatty acyl group)_z-(B)_x-(G)_y-NP

(I)，

Wherein:

z is 1, x is an integer from 2 to 4, and y is 3; or

z is 0, x is an integer from 0 to 4, and y is an integer from 1 to 3;

fatty acyl groups contain 12 to 24 (e.g., 12 to 18) carbon atoms;

b is lysine or arginine;

g is glycine;

NP is natriuretic peptide;

if present, (fatty acyl)_z-covalently linked to (B)_xThe N terminal of (1);

(fatty acyl group)_z-(B)_x-covalently linked to (G)_yThe N terminal of (1); and

(fatty acyl group)_z-(B)_x-(G)_y-covalently linked to the N-terminus of the NP.

In one embodiment, the natriuretic peptide derivative or a composition comprising the natriuretic peptide derivative increases the level of blood cGMP upon parenteral administration to a mammal to a level higher than that of natriuretic peptide NP upon parenteral administration to a mammal at an equivalent dose (e.g., a molar/Kg dose, a mg/Kg dose, or both a molar/Kg and mg/Kg dose). As used herein, because the adduct derivative has a lower mole/Kg dose when given at an equivalent mg/Kg dose, it is expected that the adduct derivative will have a higher activity at the same mole/Kg dose if the activity is equivalent at the same mg/Kg dose.

NP is typically the parent natriuretic peptide naturally occurring in living organisms. The NP may be selected from human ANP (SEQ ID1), rodent ANP (SEQ ID19), human BNP (SEQ ID41) and human ANP (SEQ ID 57).

In one embodiment, the NP is human ANP (sequence ID 1).

In one embodiment, B is lysine.

The natriuretic peptide derivative or a composition comprising the natriuretic peptide derivative according to the present disclosure may include a natriuretic peptide derivative of formula (II):

fatty acyl radical- (B)_x-(G)₃-NP

(II)，

Wherein:

fatty acyl groups have 12 to 24 (e.g., 12 to 18) carbon atoms;

b is lysine or arginine (e.g., B is lysine);

x is 2 to 4;

g is glycine;

NP is natriuretic peptide;

fatty acyl-covalently attached to (B)_xThe N terminal of (1);

fatty acyl radical- (B)_x-covalently linked to (G)₃The N terminal of (1); and

fatty acyl radical- (B)_x-(G)₃-covalently linked to the N-terminus of the NP.

When administered to a mammal, the natriuretic peptide derivative or a composition comprising the natriuretic peptide derivative typically increases blood cGMP to a level that is higher than the corresponding parent NP when administered at an equivalent dose (e.g., a molar/Kg dose, a mg/Kg dose, or both a molar/Kg and mg/Kg dose).

In one embodiment, x is 2. In one embodiment, x is 3. In one embodiment, x is 4.

In some embodiments, at fatty acyl- (B)_x-(G)₃-NP, x ═ 4; NP is optionally selected from the sequences ID1, 19, 41 and 57. For example, in some embodiments, B is lysine and NP is sequence ID 1; b is lysine, NP is sequence ID 19; b is lysine, NP is sequence ID 41; and/or B is lysine and NP is SEQ ID 57.

In some embodiments, at fatty acyl- (B)_x-(G)₃in-NPX is 3; NP is optionally selected from the sequences ID1, 19, 41 and 57. For example, in some embodiments, B is lysine and NP is sequence ID 1; b is lysine, NP is sequence ID 19; b is lysine, NP is sequence ID 41; and/or B is lysine and NP is SEQ ID 57.

In some embodiments, at fatty acyl- (B)_x-(G)₃-in NP, x ═ 2; NP is optionally selected from the sequences ID1, 19, 41 and 57. For example, in some embodiments, B is lysine and NP is sequence ID 1; b is lysine, NP is sequence ID 19; b is lysine, NP is sequence ID 41; and/or B is lysine and NP is SEQ ID 57.

In some embodiments, at fatty acyl- (B)_x-(G)₃-in NP, x ═ 1; NP is optionally selected from any one of sequences ID1, 19, 41 and 57. For example, in some embodiments, B is lysine and NP is sequence ID 1; b is lysine, NP is sequence ID 19; b is lysine, NP is sequence ID 41; and/or B is lysine and NP is SEQ ID 57.

In one embodiment, the fatty acyl group contains 18 carbon atoms.

In one embodiment, - (B)_x-(G)₃Selected from the group consisting of-KKGGG-, -KKKGGG-and-KKKKGG-.

In one embodiment, the natriuretic peptide derivative is as defined in one of sequence ID9, sequence ID10, sequence ID11, sequence ID 14, sequence ID 18, sequence ID 56, sequence ID 82, sequence ID 52, sequence ID 113, sequence ID68, sequence ID 122, and sequence ID 72; or a composition comprising a natriuretic peptide derivative comprises a natriuretic peptide derivative as defined in one of sequence ID9, sequence ID10, sequence ID11, sequence ID 14, sequence ID 18, sequence ID 56, sequence ID 82, sequence ID 52, sequence ID 113, sequence ID68, sequence ID 122, and sequence ID 72.

In one embodiment, the natriuretic peptide derivative is as defined in one of sequence ID 14, sequence ID 18, sequence ID 56, sequence ID 82, sequence ID 52, sequence ID68, sequence ID 122, and sequence ID 72; or a composition comprising a natriuretic peptide derivative comprises a natriuretic peptide derivative as defined in one of sequence ID 14, sequence ID 18, sequence ID 56, sequence ID 82, sequence ID 52, sequence ID68, sequence ID 122, and sequence ID 72.

In one embodiment, the natriuretic peptide derivative is as defined in one of sequence ID 93, sequence ID 94, sequence ID 95, sequence ID 102, sequence ID 103, sequence ID 104, sequence ID 111, sequence ID 112, sequence ID 113, sequence ID 120, sequence ID 121, and sequence ID 122; or a composition comprising a natriuretic peptide derivative comprises a natriuretic peptide derivative as defined in one of sequence ID 93, sequence ID 94, sequence ID 95, sequence ID 102, sequence ID 103, sequence ID 104, sequence ID 111, sequence ID 112, sequence ID 113, sequence ID 120, sequence ID 121, and sequence ID 122.

In one embodiment, the natriuretic peptide derivative is as defined in one of sequence ID 18, sequence ID 34, sequence ID 56, and sequence ID 72; or a composition comprising a natriuretic peptide derivative comprises a natriuretic peptide derivative as defined in one of sequence ID 18, sequence ID 34, sequence ID 56 and sequence ID 72.

In one embodiment, the natriuretic peptide derivative is as defined in one of sequence ID 14, sequence ID 30, sequence ID 52, and sequence ID 68; or a composition comprising a natriuretic peptide derivative comprises a natriuretic peptide derivative as defined in one of sequence ID 14, sequence ID 30, sequence ID 52 and sequence ID 68.

In one embodiment, the natriuretic peptide derivative is as defined in one of sequence ID10, sequence ID 30, sequence ID 52, and sequence ID 68; or a composition comprising a natriuretic peptide derivative comprises a natriuretic peptide derivative as defined in one of sequence ID10, sequence ID 30, sequence ID 52 and sequence ID 68.

In one embodiment, the natriuretic peptide derivative is as defined in one of sequence ID9, sequence ID10, sequence ID11, sequence ID 14, sequence ID 18, sequence ID 56, and sequence ID 72; or a composition comprising a natriuretic peptide derivative comprises a natriuretic peptide derivative as defined in one of sequence ID9, sequence ID10, sequence ID11, sequence ID 14, sequence ID 18, sequence ID 56, and sequence ID 72.

In one embodiment, the natriuretic peptide derivative is as defined in one of sequence ID 73, sequence ID 74, sequence ID 79, sequence ID 80, sequence ID 81, sequence ID83, sequence DI 84, and sequence ID 85; or a composition comprising a natriuretic peptide derivative comprises a natriuretic peptide derivative as defined in one of sequence ID 73, sequence ID 74, sequence ID 79, sequence ID 80, sequence ID 81, sequence ID83, sequence DI 84 and sequence ID 85.

In one embodiment, the natriuretic peptide derivative is as defined in one of sequences ID 87 to 122; or a composition comprising a natriuretic peptide derivative comprises a natriuretic peptide derivative as defined in one of the sequences ID 87 to 122.

Natriuretic peptide derivatives or compositions comprising the natriuretic peptide derivatives according to the present disclosure can include natriuretic peptide derivatives of formula (III):

(B)_x-(G)_y-NP

(III)，

wherein:

b is lysine or arginine (e.g., B is lysine);

x is 0 to 4;

g is glycine;

y is 1 to 3;

NP is natriuretic peptide; and

(B)_x-(G)_y-covalently linked to the N-terminus of the NP.

When administered to a mammal, (B)_x-(G)_yNP or a derivative comprising a natriuretic peptide (B)_x-(G)_yCompositions of-NP can increase blood cGMP to a higher level than the corresponding parent NP when administered at equivalent doses (e.g., a mole/Kg dose, a mg/Kg dose, or both a mole/Kg and mg/Kg dose).

In one embodiment, x is 0. In one embodiment, x is 1. In one embodiment, x is 2. In one embodiment, x is 3. In one embodiment, x is 4. In one embodiment, y is 1. In one embodiment, y is 2. In one embodiment, y is 3.

In some embodiments, in (B)_x-(G)_y-NP, x ═ 0; y is optionally 1, 2 or 3; NP is optionally selected from the sequences ID1, 19, 41 and 57. For example, NP has sequence ID 1; NP has sequence ID 19; NP has sequence ID 41; or sequence ID 57.

In some embodiments, in (B)_x-(G)_y-NP, y ═ 3; b is optionally lysine, x is optionally 1, 2, 3 or 4; NP is optionally selected from the sequences ID1, 19, 41 and 57. For example, NP has sequence ID 1; NP has sequence ID 19; NP has sequence ID 41; or sequence ID 57.

In one embodiment, y is 3.

In one embodiment, (B)_x-(G)_y-is selected from the group consisting of G-, GG-, GGG-, KGGG-and KKKKGGG-.

In one embodiment, the natriuretic peptide derivative is as defined in one of sequence ID2, sequence ID 3, sequence ID4, sequence ID5, sequence ID8 and sequence ID 44; or a composition comprising a natriuretic peptide derivative comprises a natriuretic peptide derivative as defined in one of sequence ID2, sequence ID 3, sequence ID4, sequence ID5, sequence ID8 and sequence ID 44.

The present disclosure also provides a pharmaceutical composition comprising a natriuretic peptide derivative as defined herein and an excipient.

The pharmaceutical composition may comprise, may consist essentially of, or may consist of one or more natriuretic peptide derivatives according to the present disclosure and excipients.

In one embodiment, the pharmaceutical composition is for use in treating a disease by administering parenterally to increase cGMP at a natriuretic peptide derivative dose of less than 1.5mg/Kg body weight per day, or at a natriuretic peptide derivative dose of less than 0.3mg/Kg body weight per day. In some embodiments, the disease is selected from hypertension, vascular congestion, and heart disease. In certain embodiments, the disease is a heart disease.

The present disclosure also provides a natriuretic peptide derivative according to the present disclosure or a composition for treating a disease comprising a natriuretic peptide derivative according to the present disclosure. The disease is selected from hypertension, vascular congestion and heart disease. In one embodiment, the disease is a heart disease.

In one embodiment, the treatment of the disease comprises parenterally administering to the patient a natriuretic peptide derivative according to the present disclosure or a composition comprising a natriuretic peptide derivative according to the present disclosure at a dose of less than 1.5mg/Kg body weight per day.

The present disclosure also provides a method of treating a disease in a patient, the method comprising parenterally administering to the patient a natriuretic peptide derivative according to the present disclosure or a composition comprising a natriuretic peptide derivative according to the present disclosure.

The method may comprise parenterally administering a pharmaceutical composition comprising, consisting essentially of, or consisting of one or more natriuretic peptide derivatives according to the present disclosure.

The natriuretic peptide derivative or a composition comprising the natriuretic peptide derivative can be administered parenterally at a dose of less than 1.5mg/Kg body weight per day, or at a dose of less than 0.3mg/Kg body weight per day to increase the patient's blood cGMP. In some embodiments, the disease is selected from hypertension, vascular congestion, and heart disease. In certain embodiments, the disease is a heart disease.

The present disclosure also provides a method of increasing blood cGMP in a patient, the method comprising parenterally administering to a patient in need thereof a natriuretic peptide derivative according to the present disclosure or a composition comprising a natriuretic peptide derivative according to the present disclosure.

The natriuretic peptide derivative or a composition comprising a natriuretic peptide derivative can be administered parenterally at a dose of less than 1.5mg/Kg body weight per day, or at a dose of less than 0.3mg/Kg body weight per day.

The present disclosure also provides the use of a natriuretic peptide derivative according to the present disclosure or a composition comprising a natriuretic peptide derivative according to the present disclosure for the preparation of a medicament for the treatment of a disease. The disease is selected from hypertension, vascular congestion and heart disease.

Detailed Description

The present disclosure relates to natriuretic peptide derivatives, or compositions thereof, having unexpectedly superior ability to increase blood cGMP and/or intracellular cGMP in vivo compared to native peptides, such as Atrial Natriuretic Peptide (ANP) or Brain Natriuretic Peptide (BNP) or C-type natriuretic peptide (CNP). As described above, ANP, BNP and CNP are peptides having cyclic structures necessary for their activities, which are possible due to the presence of disulfide bonds. Natriuretic peptide derivatives of the present disclosure can also have intramolecular disulfide bonds (between two cysteine residues) forming a cyclic structure. Intramolecular disulfide bonds can form spontaneously in dilute solution or with a suitable oxidizing agent. The formation of intramolecular disulfide bridges can be confirmed by HPLC/MS analysis.

As used herein, an addition derivative or extension derivative refers to a peptide derivative in which the main backbone amino acid sequence of the peptide remains the same but additional functional groups and/or amino acids are added to the main amino acid sequence using one or more reactive moieties in the main amino acid sequence, providing an addition derivative or extension derivative. The adduct derivatives or extended derivatives differ from truncated and/or substituted peptide derivatives in which one or more amino acids in the amino acid sequence of the main backbone of the peptide have been removed and/or replaced by different functional groups and/or amino acids, respectively.

It is believed that changes in the amino acid sequence of a peptide may have unpredictable consequences for its biological activity, and changes that retain peptide activity are not obvious and unpredictable. The present disclosure describes specific structural alterations of naturally occurring Natriuretic Peptide (NP). As used herein, a naturally occurring natriuretic peptide is referred to throughout as the "parent peptide" or "parent NP", non-limiting examples of which are SEQ ID1 (human ANP), 19 (rodent ANP), 41 (human BNP), and 57 (human CNP). In short, specific alterations in the parent NP result in a surprising unexpected enhancement or increase in potency compared to the parent NP in vivo, while other alterations result in a loss of activity, as measured by the blood cGMP response.

As used herein, the term "potency" refers to the increase in blood cGMP immediately (0-2 hours) after bolus administration relative to an equivalent dose of the parent native peptide.

As used herein, the term "apparent receptor depletion" is synonymous with "receptor depletion" and refers to the loss of the ability of the peptide to have a "sustained effect" (as seen from elevated blood cGMP) at a later time (i.e., 6 hours and later).

As used herein, the term "sustained effect" is synonymous with "sustained elevation of cGMP" and refers to the ability of the peptide to maintain elevated blood cGMP levels for at least 6 hours following a single bolus administration of the natriuretic peptide.

As used herein, the term "consisting essentially of … …" refers to a composition that includes the recited component as well as other components, provided that the other components do not materially affect the basic characteristics of the composition (e.g., bioavailability, pharmacokinetics, toxicity, and/or inhibition of activity of the induced active ingredient).

As used herein, the term "about" in describing dimensions, measurements, durations, amounts, etc., means a possible difference of +/-5%.

As used herein, the term "fatty acyl" refers to any acyl group derived from fatty acids, including saturated and unsaturated fatty acids. For example, a typical fatty acyl group derived from an unsaturated fatty acid has the formula H_2a-b(C)_a(O) -, where "a" can be 12 to 24 (e.g., 14 to 24, 16 to 24, 18 to 24, 20 to 24, 22 to 24, 12 to 22, 12 to 20, 12 to 18, 12 to 16, 12 to 14, 12, 14, 16, 18, 20, 22, or 24), "b" can be 1, 3, 5, or 7 (e.g., 1, 3, or 5; 1 or 3; or 1). This formula represents fatty acyl groups derived from saturated branched and unbranched fatty acids and fatty acids having a degree of unsaturation from none (i.e. b ═ 1) to 3 (i.e. b is 3 when the fatty acid carbon chain contains one double bond, b is 5 when the fatty acid carbon chain contains two double bonds and b is 7 when the fatty acid carbon chain contains three double bonds). For example, the natriuretic peptide derivative of formula (I) can have the formula H_2a-b(C)_a(O)-(B)_x-(G)₃NP, where "a" is from 12 to 24 and "b" may be 1, 3, 5 or 7. In some embodiments, a typical fatty acyl group derived from a saturated fatty acid has the formula CH₃(CH₂)_nC (o) -, which contains 12 to 24 carbon atoms (i.e., when n is an integer of 10 to 22). As an example, the natriuretic peptide derivative of formula (I) may have the formula CH₃(CH₂)_nC(O)-(B)_x-(G)₃NP where n is 10 to 22 (e.g. 12 to 22, 14 to 22, 16 to 22, 18 to 22, 20 to 22, 10 to 20, 10 to 18, 10 to 16, 10 to 14, 10 to 12, 10, 12, 14, 16, 18, 20 or 22). In some embodiments, n is 10 to 14, 12 to 16, 14 to 18, 16 to 20, 18 to 22, or 14 to 16. In some embodiments, the fatty acyl group contains 12 or 18 carbon atoms (i.e., n is 10 or 16). In certain embodiments, the fatty acyl group contains 14 or 20 carbon atoms (i.e., n is 12 or 18). In certain embodiments, the fatty acyl group contains 16 or 22 carbon atoms (i.e., n is 14 or 20). In certain embodiments, the fatty acyl group contains 18 or 24 carbon atoms (i.e., n is 16 or 22).

In this specification, letters in all disclosed sequences represent the conventional single letter amino acid code for naturally occurring amino acids, with upper case codes indicating L amino acids and lower case codes indicating D-amino acids. For example, glycine may be represented by G, lysine may be represented by K, and arginine may be represented by R.

By using the iso-growth power law with an index of 0.7 (i.e., the dose in other species-mouse dose/((mouse body weight/average body weight of other species))^0.7) 15mg/Kg in mice is equivalent to about 7.5mg/Kg rat dose, about 2.5mg/Kg dog dose and 1.5mg/Kg human dose. As used herein, a 15mg/Kg mouse dose is understood to be equivalent to about a 7.5mg/Kg rat dose, which is equivalent to about a 2.5mg/Kg dog dose, which is equivalent to about a 1.5mg/Kg human dose, as presented in the relevant data examples. Unless otherwise stated, the 1.5mg/Kg and 0.3mg/Kg doses in the summary of the invention and in the claims are to be understood as human doses.

Composition comprising a metal oxide and a metal oxide

The present disclosure provides natriuretic peptide derivatives of formula (I) as defined herein or compositions thereof.

In one embodiment, in formula (I), z is 1, x is 3 or 4, y is 3, and B is lysine. In formula (I), NP can be human ANP (SEQ ID 1). In formula (I), the fatty acyl group may contain 12, 18, 20, 22 or 24 carbon atoms.

The present disclosure provides natriuretic peptide derivatives of formula (II) as defined herein.

In one embodiment, in formula (II), x is 2, 3 or 4 and B is lysine. In formula (II), NP can be human ANP (SEQ ID 1). In formula (II), the fatty acyl group may contain 12 or 18 carbon atoms. Alternatively, the fatty acyl group may contain 14 or 18 carbon atoms, 16 to 18 carbon atoms, or 20 or 24 carbon atoms.

In one embodiment, the natriuretic peptide derivative is of the formula fatty acyl- (B)_x-(G)₃cGMP-enhancing derivatives of natriuretic peptides of NP, wherein:

fatty acyl groups have 12 to 24 (e.g., 12 to 18) carbon atoms;

b is lysine or arginine (e.g., B is lysine);

x is 2 to 4;

g is glycine;

NP is a parent natriuretic peptide naturally occurring in living organisms;

fatty acyl-covalently attached to (B)_xThe N-terminus of (1);

fatty acyl radical- (B)_x-covalently linked to (G)₃The N-terminus of (1);

fatty acyl radical- (B)_x-(G)₃-covalently linked to the N-terminus of the NP; and

when administered to a mammal, the natriuretic peptide derivative increases blood cGMP to a level higher than when the corresponding parent NP is administered at an equivalent dose (e.g., a molar/Kg dose, a mg/Kg dose, or both a molar/Kg and mg/Kg dose).

In some embodiments, in the formula fatty acyl- (B)_x-(G)₃-NP, x ═ 4; NP is optionally selected from the sequences ID1, 19, 41 and 57. For example, in some embodiments, B is lysine and NP is sequence ID 1; b is lysine, NP is sequence ID 19; b is lysine, NP is sequence ID 41; and/or B is lysine and NP is SEQ ID 57.

In some embodiments, in the formula fatty acyl- (B)_x-(G)₃-NP, x ═ 3; NP is optionally selected from the sequences ID1, 19, 41 and 57. For example, in some embodiments, B is lysine and NP is sequence ID 1; b is lysine, NP is sequence ID 19; b is lysine, NP is sequence ID 41; and/or B is lysine and NP is SEQ ID 57.

In some embodiments, in the formula fatty acyl- (B)_x-(G)₃-in NP, x ═ 2; NP is optionally selected from the sequences ID1, 19, 41 and 57. For example, in some embodiments, B is lysine and NP is sequence ID 1; b is lysine, NP is sequence ID 19; b is lysine, NP is sequence ID 41; and/or B is lysine and NP is SEQ ID 57.

In some embodiments, in the formula fatty acyl- (B)_x-(G)₃-in NP, x ═ 1; NP is optionally selected from any one of sequences ID1, 19, 41 and 57. For example, in some embodiments, B is lysine and NP is sequence ID 1; b is lysine, NP is sequence ID 19; b is lysine, NP is sequence ID 41; and/or B is lysine and NP is SEQ ID 57.

The present disclosure provides natriuretic peptide derivatives of formula (III) as defined herein.

In one embodiment, in formula (III), x is 0, 1, 2, 3 or 4 and B is lysine. For example, in formula (III), x may be 2 to 4, such as 3. In formula (III), NP can be human ANP (SEQ ID 1).

In one embodiment, the natriuretic peptide derivative is of formula (B)_x-(G)_ycGMP-enhancing derivatives of natriuretic peptides of NP, wherein:

b is lysine or arginine (e.g., B is lysine);

x is 0 to 4;

g is glycine;

y is 1 to 3;

NP is a parent natriuretic peptide naturally occurring in living organisms;

(B)_x-(G)_y-covalently linked to the N-terminus of the NP; and

when administered to a mammal，(B)_x-(G)_yNP increases blood cGMP to a higher level than the corresponding parent NP when administered at equivalent doses (e.g., a mole/Kg dose, a mg/Kg dose, or both a mole/Kg and mg/Kg dose).

In some embodiments, in formula (B)_x-(G)_y-NP, x ═ 0; y is optionally 1, 2 or 3; NP is optionally selected from the sequences ID1, 19, 41 and 57. For example, NP has sequence ID 1; NP has sequence ID 19; NP has sequence ID 41; or sequence ID 57.

In some embodiments, in formula (B)_x-(G)_y-NP, y ═ 3; b is optionally lysine, x is optionally 1, 2, 3 or 4; NP is optionally selected from the sequences ID1, 19, 41 and 57. For example, NP has sequence ID 1; NP has sequence ID 19; NP has sequence ID 41; or sequence ID 57.

In some embodiments, when B is lysine or arginine, (B)_xEach "B" in (a) may be the same or different. For example, (B)_xCan be K, R, RR, KK, KR, RK, RRR, KKK, KRR, RKR, RRK, KKR, KRK, RKK, RRRR, KKKKKK, KRRR, RKRR, RRKR, RRRK, KKRR, RKKR, RRKK, KRRKRK, KKKR, RKKKKKKKKK, KRKKKKKKKKKK, KRKKRK, KKRKRKRKRK, KKKR, RRRR or KKKKKKKKKK.

In some embodiments, a natriuretic peptide derivative according to the present disclosure can be a natriuretic peptide derivative as defined in any one of sequences ID2 to 18, 20 to 34, 42 to 56, and 58 to 72.

In some embodiments, a natriuretic peptide derivative according to the present disclosure can be a natriuretic peptide derivative as defined in any one of sequences ID 73 to 86, 87 to 95, 96 to 104, 105 to 113, and 114 to 122.

In one embodiment, the natriuretic peptide derivative is as defined in one of sequence ID9, sequence ID10, sequence ID11, sequence ID 14, sequence ID 18, sequence ID 56, and sequence ID 72.

In one embodiment, the natriuretic peptide derivative is as defined in one of sequence ID2, sequence ID 3, sequence ID4, sequence ID5, sequence ID8 and sequence ID 44.

In some embodimentsHaving the formula fatty acyl- (B)_x-(G)₃-NP or (B)_x-(G)_ycGMP-enhancing derivatives of the natriuretic peptide of-NP can be generally represented by the formula X-peptide.

In one aspect, provided herein are cGMP-enhancing derivatives of natriuretic peptides having the formula X-peptide, or compositions thereof, wherein the peptide moiety is selected from the group consisting of (a) ANP, (b) BNP, and (c) CNP; x is selected from G, GG, GGG, BGGG, BBGGG, BBBGGG and BBBBGGG, which is attached to the N-terminus of the peptide moiety. In some embodiments, in the cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide, the peptide moiety is selected from the group consisting of (a) ANP, (b) BNP, and (c) CNP, and X is selected from the group consisting of GG, GGG, BGGG, BBGGG, BBBGGG, and bbbbbbggg, which is attached to the N-terminus of the peptide moiety. In some embodiments, in the cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide, the peptide moiety is selected from the group consisting of (a) ANP, (b) BNP, and (c) CNP, and X is selected from the group consisting of GGG, BGGG, BBGGG, BBBGGG, and bbbbbbggg, which is attached to the N-terminus of the peptide moiety. In some embodiments, in the cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide, the peptide moiety is selected from the group consisting of (a) ANP, (b) BNP, and (c) CNP, and X is selected from the group consisting of BGGG, BBGGG, BBBGGG, and bbbbbbggg, which is attached to the N-terminus of the peptide moiety. In some embodiments, in the cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide, the peptide moiety is selected from the group consisting of (a) ANP, (b) BNP, and (c) CNP, and X is selected from the group consisting of BBGGG, BBBGGG, and bbbbbbggg, which is attached to the N-terminus of the peptide moiety. In some embodiments, in the cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide, the peptide moiety is selected from the group consisting of (a) ANP, (b) BNP, and (c) CNP, and X is selected from the group consisting of BBBGGG and bbbbbbggg, which are attached to the N-terminus of the peptide moiety. In some embodiments, in the cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide, the peptide moiety is selected from the group consisting of (a) ANP, (b) BNP, and (c) CNP, and X is BBBBGGG, which is attached to the N-terminus of the peptide moiety. In the above embodiments of the cGMP-enhancing derivatives of natriuretic peptides of the formula X-peptide, the letter G is glycine and B is lysine or arginine. In some embodiments, in any of the above embodiments of the cGMP-enhanced derivative of the natriuretic peptide of formula X-peptide, the letter G is glycine and B is lysine (see, e.g., sequence ID numbers 5-8, 21-26, 45-48, and 61-64). The cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide can increase the blood cGMP level in a mammal at a level similar to or higher than its parent natriuretic peptide (ANP, BNP, or CNP) after administration. In some embodiments, the cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide increases the blood cGMP level at a higher level than its parent natriuretic peptide (ANP, BNP, or CNP) after administration in a mammal. The parent natriuretic peptides ANP, BNP, and CNP can have sequences (e.g., sequences ID1, 19, 41, or 57) found naturally in vertebrates, or more specifically, found in mammalian natriuretic peptides.

In another aspect, provided herein are cGMP-enhancing derivatives of natriuretic peptides having the formula X-peptide, or compositions thereof, wherein the peptide moiety is selected from the group consisting of (a) ANP, (b) BNP, and (c) CNP, and X is selected from the group consisting of CH₃(CH₂)₁₀COKKKKGGG、CH₃(CH₂)₁₂COKKKKGGG、CH₃(CH₂)₁₄COKKKKGGG and CH₃(CH₂)₁₆Cokkkkkgg attached to the N-terminus of the peptide moiety. In some embodiments, in the cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide, the peptide moiety is selected from the group consisting of (a) ANP, (b) BNP, and (c) CNP, and X is selected from the group consisting of CH₃(CH₂)₁₀COKKKKGGG and CH₃(CH₂)₁₆Cokkkkkgg attached to the N-terminus of the peptide moiety. In some embodiments, in the cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide, the peptide moiety is selected from the group consisting of (a) ANP, (b) BNP, and (c) CNP, and X is CH₃(CH₂)₁₆Cokkkkkgg attached to the N-terminus of the peptide moiety. In the above embodiments of the cGMP-enhancing derivatives of natriuretic peptides of the formula X-peptide, the letter G is glycine, K is lysine, CH₃(CH₂)_{[10, 12, 14 or 16 ]]}The CO group is a standard chemical formula for alkylcarbonyl, subscript [10, 12, 14 or 16]Represents CH in the alkyl chain₂The number of groups. The cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide can increase the blood cGMP level in a mammal at a level similar to or higher than its parent natriuretic peptide (ANP, BNP, or CNP) after administration. In some embodiments, the cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide increases the blood cGMP level at a higher level than its parent natriuretic peptide (ANP, BNP, or CNP) after administration in a mammal. The parent natriuretic peptides ANP, BNP andthe CNP may have a sequence (e.g., sequence ID1, 19, 41, or 57) found naturally in vertebrates, or more specifically in mammalian natriuretic peptides.

In yet another aspect, provided herein are cGMP-enhancing derivatives of natriuretic peptides having the formula X-peptide, or compositions thereof, wherein the peptide moiety is selected from the group consisting of (a) ANP, (b) BNP, and (c) CNP, and X is selected from the group consisting of CH₃(CH₂)₁₀CORRRRGGG、CH₃(CH₂)₁₂CORRRRGGG、CH₃(CH₂)₁₄CORRRRGGG and CH₃(CH₂)₁₆CORRRRGGG attached to the N-terminus of the peptide moiety. In some embodiments, in the cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide, the peptide moiety is selected from the group consisting of (a) ANP, (b) BNP, and (c) CNP, and X is selected from the group consisting of CH₃(CH₂)₁₀CORRRRGGG and CH₃(CH₂)₁₆CORRRRGGG attached to the N-terminus of the peptide moiety. In some embodiments, in the cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide, the peptide moiety is selected from the group consisting of (a) ANP, (b) BNP, and (c) CNP, and X is CH₃(CH₂)₁₆CORRRRGGG attached to the N-terminus of the peptide moiety. In the above embodiments of the cGMP-enhancing derivatives of natriuretic peptides of the formula X-peptide, the letter G is glycine, R is arginine, CH₃(CH₂)_{[10, 12, 14 or 16 ]]}The CO group is the standard formula for alkylcarbonyl and [10, 12, 14 or 16]Represents CH in the alkyl chain₂The number of groups. The cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide can increase the blood cGMP level in a mammal at a level similar to or higher than its parent natriuretic peptide (ANP, BNP, or CNP) after administration. In some embodiments, the cGMP-enhancing derivative of a natriuretic peptide of the formula X-peptide increases the blood cGMP level at a higher level than its parent natriuretic peptide (ANP, BNP, or CNP) after administration in a mammal. The parent natriuretic peptides ANP, BNP, and CNP can have sequences (e.g., sequences ID1, 19, 41, or 57) found naturally in vertebrates, or more specifically, found in mammalian natriuretic peptides.

In some embodiments, provided herein are cGMP-enhancing derivatives of natriuretic peptides having the formula X-peptide; or a composition comprising, consisting essentially of, or consisting of a cGMP-enhancing derivative of a natriuretic peptide having the formula X-peptide; wherein the peptide moiety is ANP, BNP or CNP; x is CH attached to the N-terminus of the peptide moiety₃(CH₂)_pCOKKKGGG (K ═ lysine, G ═ glutamic acid, CH)₃(CH₂)_pThe CO group is a standard formula for alkylcarbonyl where p is 10 to 22 (e.g., or 10 to 16) and represents a repeating CH in the alkyl chain₂The number of groups). In some embodiments, the peptide moiety is ANP or BNP. In some embodiments, the peptide moiety is ANP. In some embodiments, the peptide moiety is BNP. In some embodiments, the peptide moiety is CNP. The X-peptide can increase the level of blood cGMP at a level similar to or higher (e.g., higher) than its parent natriuretic peptide following administration in a mammal. In some embodiments, the parent natriuretic peptide is CNP having the sequence GLSKGCFGLKLDRIGSMSGLGC (sequence ID57), and some representative cGMP-enhancing derivatives of natriuretic peptides are the sequences ID 83-85. As an example, when the X-peptide is sequence ID83 (the peptide moiety is CNP, and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₀COKKKGGG), the X-peptide increases the level of blood cGMP at a level similar to or higher than (e.g., higher than) its parent natriuretic peptide CNP GLSKGCFGLKLDRIGSMSGLGC (sequence ID57) after administration in a mammal. As another example, when the X-peptide is sequence ID85 (peptide moiety is CNP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₆Cokkkgg), the X-peptide is similar to or higher (e.g., higher) than its parent natriuretic peptide CNP GLSKGCFGLKLDRIGSMSGLGC (sequence ID57) after administration in a mammalLevels increase blood cGMP levels. In some embodiments, the parent natriuretic peptide is ANP having the sequence SLRRSSCFGGRMDRIGAQSGLGCNSFRY (sequence ID1), and cGMP-enhancing derivatives of some representative natriuretic peptides are the sequences ID 11-14. As an example, when the X-peptide is sequence ID11 (the peptide moiety is ANP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₀COKKKGGG), the X-peptide increases the level of blood cGMP at a level similar to or higher than (e.g., higher than) its parent natriuretic peptide ANP SLRRSSCFGGRMDRIGAQSGLGCNSFRY (sequence ID1) after administration in a mammal. As an example, when the X-peptide is sequence ID 14 (the peptide moiety is ANP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₆COKKKGGG), the X-peptide increases the level of blood cGMP at a level similar to or higher than (e.g., higher than) its parent natriuretic peptide ANP SLRRSSCFGGRMDRIGAQSGLGCNSFRY (sequence ID1) after administration in a mammal. In some embodiments, the parent natriuretic peptide is ANP having the sequence SLRRSSCFGGRIDRIGAQSGLGCNSFRY (sequence ID19), and some representative cGMP-enhancing derivatives of natriuretic peptides are sequence ID 27-30. As an example, when the X-peptide is sequence ID 27 (the peptide moiety is ANP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₀COKKKGGG), the X-peptide increases the level of blood cGMP at a level similar to or higher than (e.g., higher than) its parent natriuretic peptide ANP SLRRSSCFGGRIDRIGAQSGLGCNSFRY (sequence ID19) after administration in a mammal. As an example, when the X-peptide is sequence ID 30 (the peptide moiety is ANP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₆COKKKGGG), the X-peptide increases the level of blood cGMP at a level similar to or higher than (e.g., higher than) its parent natriuretic peptide ANP SLRRSSCFGGRIDRIGAQSGLGCNSFRY (sequence ID19) after administration in a mammal. In some embodiments, the parent natriuretic peptide is BNP having the sequence SPKMVQGSGCFGRKMDRISSSSGLGCKVLRRH (sequence ID41), and some representative cGMP-enhancing derivatives of natriuretic peptides are the sequences ID 49-52. As an example, when the X-peptide is sequence ID 49 (the peptide moiety is BNP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₀COKKKGGG), the X-peptide increases the level of blood cGMP at a level similar to or higher (e.g., higher) than its parent natriuretic peptide BNP spkmvqgsgcfgrkmdris sssglgckvlrrh (sequence ID41) after administration in a mammal. As an example, when the X-peptide is sequence ID 52 (the peptide moiety is BNP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₆COKKKGGG), the X-peptide increases the level of blood cGMP at a level similar to or higher (e.g., higher) than its parent natriuretic peptide BNP spkmvqgsgcfgrkmdris sssglgckvlrrh (sequence ID41) after administration in a mammal. In some embodiments, the parent natriuretic peptide is CNP having the sequence GLSKGCFGLKLDRIGSMSGLGC (sequence ID57), and cGMP-enhancing derivatives of some representative natriuretic peptides are sequence ID 65-68. As an example, when the X-peptide is sequence ID 65 (peptide moiety is CNP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₀COKKKGGG), the X-peptide increases the level of blood cGMP at a level similar to or higher than (e.g., higher than) its parent natriuretic peptide CNP GLSKGCFGLKLDRIGSMSGLGC (sequence ID57) after administration in a mammal. As an example, when the X-peptide is sequence ID68 (peptide moiety is CNP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₆COKKKGGG), the X-peptide increases the level of blood cGMP at a level similar to or higher than (e.g., higher than) its parent natriuretic peptide CNP GLSKGCFGLKLDRIGSMSGLGC (sequence ID57) after administration in a mammal.

In some embodiments, provided herein are cGMP-enhancing derivatives of natriuretic peptides having the formula X-peptide; or a composition comprising, consisting essentially of, or consisting of a cGMP-enhancing derivative of a natriuretic peptide having the formula X-peptide; wherein the peptide moiety is ANP, BNP or CNP; x is CH attached to the N-terminus of the peptide moiety₃(CH₂)_pCOKKKKGGG (K ═ lysine, G ═ glutamic acid, CH)₃(CH₂)_pThe CO group is a standard formula for alkylcarbonyl where p is 10 to 22 (e.g., or 10 to 16) and represents a repeating CH in the alkyl chain₂Of radicalsNumber). In some embodiments, the peptide moiety is ANP or BNP. In some embodiments, the peptide moiety is ANP. In some embodiments, the peptide moiety is BNP. In some embodiments, the peptide moiety is CNP. The X-peptide can increase the level of blood cGMP at a level similar to or higher (e.g., higher) than its parent natriuretic peptide following administration in a mammal. In some embodiments, the parent natriuretic peptide is ANP having the sequence SLRRSSCFGGRMDRIGAQSGLGCNSFRY (sequence ID1), and cGMP-enhancing derivatives of some representative natriuretic peptides are the sequences ID 15-18. As an example, when the X-peptide is sequence ID15 (the peptide moiety is ANP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₀Cokkkkkkggg), the X-peptide increases the level of blood cGMP at a level similar to or higher (e.g., higher) than its parent natriuretic peptide ANP SLRRSSCFGGRMDRIGAQSGLGCNSFRY (sequence ID1) after administration in a mammal. As an example, when the X-peptide is sequence ID 18 (the peptide moiety is ANP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₆Cokkkkkkggg), the X-peptide increases the level of blood cGMP at a level similar to or higher (e.g., higher) than its parent natriuretic peptide ANP SLRRSSCFGGRMDRIGAQSGLGCNSFRY (sequence ID1) after administration in a mammal. In some embodiments, the parent natriuretic peptide is ANP having the sequence SLRRSSCFGGRIDRIGAQSGLGCNSFRY (sequence ID19), and cGMP-enhancing derivatives of some representative natriuretic peptides are sequences ID 31-34. As an example, when the X-peptide is sequence ID 31 (the peptide moiety is ANP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₀Cokkkkkkggg), the X-peptide increases the level of blood cGMP at a level similar to or higher (e.g., higher) than its parent natriuretic peptide ANP SLRRSSCFGGRIDRIGAQSGLGCNSFRY (sequence ID19) after administration in a mammal. As an example, when the X-peptide is sequence ID 34 (the peptide moiety is ANP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₆Cokkkkkkggg), the X-peptide increases the level of blood cGMP at a level similar to or higher (e.g., higher) than its parent natriuretic peptide ANP SLRRSSCFGGRIDRIGAQSGLGCNSFRY (sequence ID19) after administration in a mammal. In some embodimentsThe parent natriuretic peptide is BNP having the sequence SPKMVQGSGCFGRKMDRISSSSGLGCKVLRRH (sequence ID41), and some representative cGMP-enhancing derivatives of natriuretic peptides are the sequences ID 53-56. As an example, when the X-peptide is the sequence ID53 (the peptide moiety is BNP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₀Cokkkkkkggg), the X-peptide increases the level of blood cGMP at a level similar to or higher (e.g., higher) than its parent natriuretic peptide BNP SPKMVQGSGCFGRKMDRISSSSGLGCKVLRRH (sequence ID41) after administration in a mammal. As an example, when the X-peptide is sequence ID 56 (the peptide moiety is BNP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₆Cokkkkkkggg), the X-peptide increases the level of blood cGMP at a level similar to or higher (e.g., higher) than its parent natriuretic peptide BNP SPKMVQGSGCFGRKMDRISSSSGLGCKVLRRH (sequence ID41) after administration in a mammal. In some embodiments, the parent natriuretic peptide is CNP having the sequence GLSKGCFGLKLDRIGSMSGLGC (sequence ID57), and cGMP-enhancing derivatives of some representative natriuretic peptides are the sequences ID 69-72. As an example, when the X-peptide is sequence ID 69 (peptide moiety is CNP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₀Cokkkkkkggg), the X-peptide increases the level of blood cGMP at a level similar to or higher (e.g., higher) than its parent natriuretic peptide CNP GLSKGCFGLKLDRIGSMSGLGC (sequence ID57) after administration in a mammal. As an example, when the X-peptide is sequence ID 72 (peptide moiety is CNP and X is CH attached to the N-terminus of the peptide moiety)₃(CH₂)₁₆Cokkkkkkggg), the X-peptide increases the level of blood cGMP at a level similar to or higher (e.g., higher) than its parent natriuretic peptide CNP GLSKGCFGLKLDRIGSMSGLGC (sequence ID57) after administration in a mammal.

Pharmaceutical compositions and methods of use

The present disclosure provides a pharmaceutical composition comprising a natriuretic peptide according to the present disclosure and an excipient. The pharmaceutical composition may be a pharmaceutical composition comprising, consisting essentially of, or consisting of one or more of the above-described natriuretic peptide derivatives and excipients for use in the treatment of a disease by increasing cGMP by parenteral administration at a dose of the natriuretic peptide derivative of less than 1.5mg/Kg body weight per day, or at a dose of the natriuretic peptide derivative of less than 0.3mg/Kg body weight per day.

In some embodiments, the dose of the natriuretic peptide derivative is greater than 0.0001mg/Kg body weight per day. For example, the dose of natriuretic peptide derivatives may be greater than 0.0001mg/Kg and/or less than 1.5mg/Kg of body weight per day. In some embodiments, the dose of the natriuretic peptide derivative is greater than 0.0001mg/Kg and/or less than 1.0mg/Kg of body weight per day, or greater than 0.0001mg/Kg and/or less than 0.5mg/Kg of body weight per day. In some embodiments, the dose of the natriuretic peptide derivative is greater than 0.0001mg/Kg and/or less than 0.3mg/Kg of body weight per day.

In some embodiments, the disease is selected from hypertension, vascular congestion, and heart disease. In certain embodiments, the disease is a heart disease.

In yet another aspect, the present disclosure relates to a method of treating a disease in a patient, said method comprising parenterally administering to the patient one or more of the above natriuretic peptide derivatives or a pharmaceutical composition comprising, consisting essentially of, or consisting of one or more of the above natriuretic peptide derivatives at a dose of natriuretic peptide derivatives less than 1.5mg/Kg body weight per day or at a dose of natriuretic peptide derivatives less than 0.3mg/Kg body weight per day, said method consisting essentially of parenterally administering to the patient one or more of the above natriuretic peptide derivatives or a pharmaceutical composition comprising one or more of the above natriuretic peptide derivatives at a dose of natriuretic peptide derivatives less than 1.5mg/Kg body weight per day or at a dose of natriuretic peptide derivatives less than 0.3mg/Kg body weight per day, A pharmaceutical composition consisting essentially of, or consisting of one or more of the above natriuretic peptide derivatives, or said method consisting of parenterally administering to a patient one or more of the above natriuretic peptide derivatives or a pharmaceutical composition comprising, consisting essentially of, or consisting of one or more of the above natriuretic peptide derivatives at a daily dosage of natriuretic peptide derivatives of less than 1.5mg/Kg body weight or at a daily dosage of natriuretic peptide derivatives of less than 0.3mg/Kg body weight to increase the blood cGMP of the patient. In some embodiments, the disease is selected from hypertension, vascular congestion, and heart disease. In certain embodiments, the disease is a heart disease.

In yet another aspect, the present disclosure relates to a method of increasing blood cGMP in a patient, the method comprising parenterally administering to a patient in need thereof one or more of the above natriuretic peptide derivatives or a pharmaceutical composition comprising, consisting essentially of, or consisting of one or more of the above natriuretic peptide derivatives at a dose of natriuretic peptide derivatives less than 1.5mg/Kg body weight per day or at a dose of natriuretic peptide derivatives less than 0.3mg/Kg body weight per day, the method consisting essentially of parenterally administering to a patient in need thereof one or more of the above natriuretic peptide derivatives or a pharmaceutical composition comprising one or more of the above natriuretic peptide derivatives at a dose of natriuretic peptide derivatives less than 1.5mg/Kg body weight per day or at a dose of natriuretic peptide derivatives less than 0.3mg/Kg body weight per day, a method of increasing blood cGMP in a patient in need thereof, a method of parenterally administering to a patient in need thereof one or more of the above natriuretic peptide derivatives or a pharmaceutical composition comprising one or more of the above natriuretic peptide derivatives, A pharmaceutical composition consisting essentially of, or consisting of one or more of the above natriuretic peptide derivatives, or said method consisting of parenterally administering to a patient in need thereof one or more of the above natriuretic peptide derivatives or a pharmaceutical composition comprising, consisting essentially of, or consisting of one or more of the above natriuretic peptide derivatives at a dose of natriuretic peptide derivatives per day of less than 1.5mg/Kg body weight or at a dose of natriuretic peptide derivatives per day of less than 0.3mg/Kg body weight.

In yet another aspect, the present disclosure describes pharmaceutical compositions comprising any of the foregoing natriuretic peptide cGMP-enhanced derivatives of formula X-peptide with one or more suitable excipients consisting essentially of, or consisting of any of the foregoing natriuretic peptide cGMP-enhanced derivatives of formula X-peptide with one or more suitable excipients for use in treating diseases that can be alleviated by cGMP (e.g., blood cGMP) increase in a mammal by administering the cGMP-enhanced derivatives parenterally and/or subcutaneously at a dose of less than 1.5mg/Kg body weight per day (e.g., less than 0.3mg/Kg body weight per day). Also provided are methods of treating a disease that can be alleviated by increasing cGMP (e.g., blood cGMP) and/or increasing cGMP (e.g., blood cGMP) comprising parenterally and/or subcutaneously administering a cGMP-enhancing derivative of any of the above natriuretic peptides having the formula X-peptide at a dose (cGMP-enhancing derivative) of less than 1.5mg/Kg body weight per day (e.g., less than 0.3mg/Kg body weight per day) with one or more suitable excipients consisting essentially of parenterally and/or subcutaneously administering a cGMP-enhancing derivative of any of the above natriuretic peptides having the formula X-peptide at a dose (cGMP-enhancing derivative) of less than 1.5mg/Kg body weight per day (e.g., less than 0.3mg/Kg body weight per day) with one or more suitable excipients, or consisting of administering a cGMP-enhancing derivative of less than 1.5mg/Kg body weight per day (e.g., less than 0.3mg/Kg body weight per day) of a (cGMP-enhanced derivative) dose consisting of a cGMP-enhanced derivative of any of the natriuretic peptides mentioned above having the formula X-peptide and one or more suitable excipients). In some embodiments, diseases that can be alleviated by increasing cGMP (e.g., blood cGMP) include, consist essentially of, or consist of hypertension, vascular congestion, heart disease; and the treatment may comprise parenteral and/or subcutaneous administration of any of the cGMP-enhancing derivatives of natriuretic peptide having the formula X-peptide described above with one or more suitable excipients at a dose of (cGMP-enhancing derivative) less than 1.5mg/Kg body weight per day (e.g., less than 0.3mg/Kg body weight per day), consisting essentially of parenteral and/or subcutaneous administration of any of the cGMP-enhancing derivatives of natriuretic peptide having the formula X-peptide described above with one or more suitable excipients at a dose of (cGMP-enhancing derivative) less than 1.5mg/Kg body weight per day (e.g., less than 0.3mg/Kg body weight per day), or consists of parenterally and/or subcutaneously administering a cGMP-enhanced derivative of any of the above natriuretic peptides having the formula X-peptide at a dose of (cGMP-enhanced derivative) less than 1.5mg/Kg body weight per day (e.g., less than 0.3mg/Kg body weight per day) with one or more suitable excipients. In some embodiments, the cGMP-enhancing derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the group consisting of sequences ID 2-18, 20-35, 37, 38, 42-56, and 58-85, administered at the dosages described above. In some embodiments, the cGMP-enhancing derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or method of treatment is selected from the group consisting of sequences ID 2-8, 20-26, 42-48, and 58-64, administered at the dosages described above. In some embodiments, the cGMP-enhancing derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the group consisting of sequences ID 9-18, 27-35, 37, 38, 49-56, and 65-122, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the group consisting of sequences ID9, 10, 73-89, 96-98, 105-107 and 114-116, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the sequences ID9, 75, 79 and 83, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the group consisting of sequences ID10, 78, 82, and 86, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID10, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 78, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or method of treatment is sequence ID 82, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 86, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the group consisting of sequences ID11-14, 27-30, 49-52, 65-68, 90-92, 99-101, 108-110, and 117-119, and is administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the group consisting of sequences ID11, 14, 27, 30, 49, 52, 65, and 68, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the sequences ID 96-122, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the group consisting of SEQ ID 102-104, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the sequences ID11, 27, 49 and 65, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID11, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 27, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 49, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or method of treatment is sequence ID 65, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the sequences ID 14, 30, 52 and 68, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 14, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or method of treatment is sequence ID 30, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 52, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID68, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the group consisting of sequences ID 15-18, 31-34, 53-56, 69-72, 93-95, 102-104, 111-113, and 120-122, and is administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the group consisting of sequences ID15, 18, 31, 34, 53, 56, 69, and 72, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the sequences ID15, 31, 53 and 69, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID15, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 31, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID53, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 69, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the sequences ID 18, 34, 56 and 72, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 18, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 34, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 56, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 72, administered at the dosages described above.

In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the sequences ID 93, 102, 111 and 120, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 93, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or method of treatment is sequence ID 102, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 111, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or method of treatment is sequence ID 120, administered at the dosages described above.

In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the sequences ID 94, 103, 112 and 121, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 94, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 103, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or method of treatment is sequence ID 112, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or method of treatment is sequence ID 121, administered at the dosages described above.

In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is selected from the sequences ID 95, 104, 113 and 122, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 95, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or method of treatment is sequence ID 104, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 113, administered at the dosages described above. In some embodiments, the cGMP-enhanced derivative of a natriuretic peptide having the formula X-peptide used in the pharmaceutical composition or in the method of treatment is sequence ID 122, administered at the dosages described above.

The following examples are introduced for the purpose of illustration and not limitation of the described embodiments.

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