CRHR2 PEPTIDE AGONISTS AND USES THEREOF

• US 20100130424A1
• Filed: 11/04/2009
• Published: 05/27/2010
• Est. Priority Date: 11/04/2008
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: MORENO, VERONICA, SWANSON, RONALD V., SHANKLEY, NIGEL P., GENGO, PETER
• Granted Patent: US 10,040,838 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/57509 Corticotropin releasing factor [CRF] (Urotensin)

Abstract

The present invention relates to novel peptides that are selective corticotrophin releasing hormone receptor type 2 (CRHR2) agonists and compositions thereof for the treatment, amelioration or inhibition of cardiovascular conditions, including but not limited to heart failure. The novel peptide agonist preferably comprise modifications that include pegylated peptides. Furthermore, the present invention also relates to methods for the treatment and prevention of a disease or disorder related to CRHR2 activity.

Claims

1. A peptide having agonist activity towards corticotrophin releasing hormone receptor type 2, said peptide comprising the amino acid sequence of

2. The peptide of claim 1, wherein said substitution is selected from the group consisting of:

X for L at position 1;

X for S at position 2;

X for D at position 4;

X for V at position 5;

X for P at position 6;

X for T at position 7;

X for N at position 8;

X for I at position 9;

X for M at position 10;

X for N at position 11;

X for L at position 12;

X for L at position 13;

X for F at position 14;

X for N at position 15;

X for I at position 16;

X for A at position 17;

X for K at position 18;

X for A at position 19;

X for K at position 20;

X for N at position 21;

X for L at position 22;

X for R at position 23;

X for A at position 24;

X for Q at position 25;

X for A at position 26;

X for A at position 27;

X for A at position 28;

X for A at position 30;

X for H at position 31;

X for L at position 32;

X for A at position 34;

X for Q at position 35; and

X for I at position 36.

3. The peptide of claim 1, wherein said peptide is selected from the group consisting of:

4. The peptide of claim 1, wherein the amino acid sequence is selected from the group consisting of SEQ ID NO.s 17, 18, 20, 21, 25, 26, 27, 29, 32, 33, 34, 36, and 41;

and X is cysteine.

5. A conjugate comprising the peptide of claim 1 and a linker attached to the X of said peptide.

6. The conjugate of claim 5, wherein X is cysteine.

7. The conjugate of claim 5, wherein said linker is acetamide or N-ethylsuccinimide.

8. The conjugate of claim 5 further comprising polyethylene glycol (PEG) attached to said linker, wherein said PEG has a molecular weight of not more than about 80 kDa.

9. The conjugate of claim 8, wherein said linker is acetamide.

10. The conjugate of claim 8, wherein said PEG has a molecular weight that is selected from the group of weights consisting of about 2 kDa, about 5 kDa, about 12 kDa, about 20 kDa, about 30 kDa, and about 40 kDa.

11. The conjugate of claim 5, wherein said PEG is branched or linear.

12. The conjugate of claim 5, wherein said PEG further comprises a reactive group.

13. The conjugate of claim 12, wherein said reactive group is N-ethylmaleimide.

14. The peptide of claim 1, wherein said peptide has an amino acid sequence selected from the group consisting of SEQ ID NO.s 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 36, 37, 39, 40, and 41.

15. A conjugate having the formula of:

16. A conjugate of claim 6 having the formula of:

17. A conjugate of claim 6 having the formula of:

18. A conjugate of claim 6 having the formula of:

19. The peptide of claim 1, wherein said peptide has an amino acid sequence of SEQ ID NO. 29.

20. The conjugate of claim 16, wherein n is an integer of about 460, and R is a peptide having the amino acid sequence of SEQ ID NO. 29.

21. The conjugate of claim 18, wherein n is an integer of about 460, and R is a peptide having the amino acid sequence of SEQ ID NO. 29.

22. A polynucleotide encoding a peptide of claim 1.

23. A pharmaceutical composition comprising (a) a peptide of claim 1;

and (b) a pharmaceutically acceptable excipient.

24. The pharmaceutical composition of claim 23 comprising the peptide of amino acid sequence SEQ ID NO. 29.

25. A pharmaceutical composition comprising (a) the conjugate of claim 5;

and (b) a pharmaceutically acceptable excipient.

26. A pharmaceutical composition comprising (a) the conjugate of claim 20;

and (b) a pharmaceutically acceptable excipient.

27. A pharmaceutical composition comprising (a) the conjugate of claim 21;

and (b) a pharmaceutically acceptable excipient.

28. A monoclonal antibody that specifically binds to a peptide comprising the amino acid sequence of said peptide of claim 1.

29. The monoclonal antibody of claim 28, wherein said peptide is pegylated.

30. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by corticotrophin releasing hormone receptor 2 activity selected from the group consisting of metabolic disease and heart failure, comprising administering to a subject in need of such treatment a therapeutically effective amount of a peptide of claim 1.

31. A method according to claim 30, wherein the disease, disorder, or medical condition is diabetes.

32. A method according to claim 30, wherein the disease, disorder, or medical condition is heart failure.