PYY Agonists and Uses Thereof

• US 20090170778A1
• Filed: 02/26/2009
• Published: 07/02/2009
• Est. Priority Date: 02/04/2005
• Status: Abandoned Application

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Siegel, Ned R., Summers, Neena L., Nardone, Nancy A., Finn, Rory R.
• Application Number:
  US12/393,420
• Publication Number:
  US 20090170778A1
• 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: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695

Abstract

The invention provides PYY_3-36 variants and pegylated derivatives thereof and compositions and methods useful in the treatment of conditions modulated by an NPY Y2 receptor agonist.

Claims

1. The polypeptide (E10C)hPYY_3-36 having the amino acid sequence IKPEAPGCDASPEELNRYYASLRHYLNLVTRQRY-NH₂ [SEQ ID No.:

3] or a pharmaceutically acceptable salt thereof.

2. The polypeptide (D11C)hPYY_3-36 having the amino acid sequence IKPEAPGECASPEELNRYYASLRHYLNLVTRQRY-NH₂ [SEQ ID No.:

4] or a pharmaceutically acceptable salt thereof.

3. A conjugate comprising a polyethylene glycol (PEG) and the polypeptide (E10C)hPYY_3-36 having the amino acid sequence IKPEAPGCDASPEELNRYYASLRHYLNLVTRQRY-NH₂ [SEQ ID No.:

3] or (D11C)hPYY_3-36 having the amino acid sequence IKPEAPGECASPEELNRYYASLRHYLNLVTRQRY-NH₂ [SEQ ID No.;

4].

4. The conjugate of claim 3 having Formula 3

5. The conjugate of claim 4 wherein the mPEG is linear.

6. The conjugate of claim 5 having Formula 4

7. The conjugate of claim 6 wherein the (OCH₂CH₂)_n moiety has a weight average molecular weight of about 30 kD.

8. The conjugate of claim 5 having Formula 4

9. The conjugate of claim 8 wherein the (OCH₂CH₂)_n moiety has a weight average molecular weight of about 20 kD.

10. The conjugate of claim 5 having Formula 4

11. The conjugate of claim 10 wherein the (OCH₂CH₂)_n moiety has a weight average molecular weight of about 30 kD.

12. The conjugate of claim 4 wherein the mPEG is branched.

13. The conjugate of claim 12 wherein the mPEG is glycerol-branched.

14. The conjugate of claim 13 having Formula 5

15. The conjugate of claim 14 wherein each (OCH₂CH₂)_m moiety has a weight average molecular weight in the range of about 20 kD to 22 kD.

16. The conjugate of claim 13 having Formula 5

17. The conjugate of claim 16 wherein each (OCH₂CH₂)_m moiety has a weight average molecular weight in the range of about 20 kD to 22 kD.

18. A glycerol-branched 43 k mPEG maleimide (E10C)hPYY_3-36 having the amino acid sequence IKPEAPGCDASPEELNRYYASLRHYLNLVTRQRY-NH₂ [SEQ ID No.:

3] conjugate having Formula 5

19. A glycerol-branched 43 k mPEG maleimide (D11C)hPYY_3-36 having the amino acid sequence IKPEAPGECASPEELNRYYASLRHYLNLVTRQRY-NH₂ [SEQ ID No.:

4] conjugate Formula 5

20. A pharmaceutical composition comprising the polypeptide (E10C)hPYY_3-36 having the amino acid sequence IKPEAPGCDASPEELNRYYASLRHYLNLVTRQRY-NH₂ SEQ ID NO:

3, or the polypeptide of (D11C)hPYY_3-36 having the amino acid sequence IKPEAPGECASPEELNRYYASLRHYLNLVTRQRY-NH₂ SEQ ID NO;

4, or the conjugate of Formula 3

21. The pharmaceutical composition of claim 20 further comprising a second agent that is an anti-obesity agent.

22. The pharmaceutical composition of claim 20 comprising the conjugate having Formula 4.

23. The pharmaceutical composition of claim 20 comprising the conjugate having Formula 4

24. The pharmaceutical composition of claim 20 comprising the conjugate having Formula 4

25. The pharmaceutical composition of claim 20 comprising the conjugate having Formula 5

26. A method of reducing weight gain in an obese or overweight mammal in need of such treatment, which comprises peripherally administering to the mammal a therapeutically effective amount of the polypeptide (E10C)hPYY_3-36 having the amino acid sequence IKPEAPGCDASPEELNRYYASLRHYLNLVTRQRY-NH₂ SEQ ID NO:

3, or the polypeptide (D11C)hPYY_3-36 having the amino acid sequence IKPEAPGECASPEELNRYYASLRHYLNLVTRQRY-NH₂ SEQ ID NO;

4, or the conjugate of Formula 3

27. The method of claim 26, comprising administering a second agent that is an anti-obesity agent.

28. The method of claim 26, comprising peripherally administering the conjugate having Formula 4

29. The method of claim 26, comprising peripherally administering the conjugate having Formula 4

30. The method of claim 26, comprising peripherally administering the conjugate having Formula 4

31. The method of claim 26, comprising peripherally administering the conjugate having Formula 5

32. A method of weight gain, reducing food intake or reducing caloric intake in a mammal which comprises peripherally administering to the mammal the polypeptide (E10C)hPYY_3-36 having the amino acid sequence IKPEAPGCDASPEELNRYYASLRHYLNLVTRQRY-NH₂ SEQ ID NO:

3, or the polypeptide (D11C)hPYY_3-36 having the amino acid sequence IKPEAPGECASPEELNRYYASLRHYLNLVTRQRY-NH₂ SEQ ID NO;

4, or the conjugate of Formula 3

33. The method of claim 32, comprising administering a second agent that is an anti-obesity agent.

34. The method of claim 32, comprising peripherally administering the conjugate having Formula 4

35. The method of claim 32, comprising peripherally administering the conjugate having Formula 4

36. The method of claim 32, comprising peripherally administering the conjugate having Formula 4

37. The method of claim 32, comprising peripherally administering the conjugate having Formula 5

38-40. -40. (canceled)