Insulinotropic hormones and uses thereof

• US 5,958,909 A
• Filed: 11/20/1996
• Issued: 09/28/1999
• Est. Priority Date: 05/05/1986
• Status: Expired due to Term

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Habener, Joel F.
• Primary Examiner(s): MINNIFIELD, NITA M
• Application Number:
  US08/749,762
• Time in Patent Office: 1,042 Days
• Field of Search: 514/120, 514/12, 514/866, 530/324, 530/303, 530/308
• US Class Current: 514/120
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

Derivatives of glucagon-like peptide I (GLP-1) and especially GLP-1(7-36) have been found to have insulinotropic activity. The invention pertains to the use of GLP-1(7-36) for the treatment of type II diabetes mellitus.

Claims

1. A method for enhancing the expression of insulin in a pancreatic β

-type islet cell, said method comprising

providing to a mammalian pancreatic β

-type islet cell an effective amount of an insulinotropic molecule selected from the group consisting of;

(A) a peptide having the amino acid sequence;

His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly; and

(B) a derivative of said peptide (A), wherein said derivative is selected from the group consisting of;

(1) a pharmaceutically acceptable acid addition salt of said peptide;

(2) a pharmaceutically acceptable carboxylate salt of said peptide;

(3) a pharmaceutically acceptable lower alkyl ester of said peptide; and

(4) a pharmaceutically acceptable amide of said peptide;

wherein said molecule is substantially free of natural contaminants, and has an insulinotropic activity which exceeds the insulinotropic activity of glucagon-like peptide-1(1-36) (GLP-1(1-36)), or glucagon-like peptide-1(1-37) (GLP-1(1-37)).

2. The method of claim 1, wherein said mammal is a human.

5. The method of any one of claims 1, 2, 3 or 4, wherein said insulinotropic molecule is said derivative (B) of said peptide.

6. The method of claim 5, wherein said derivative (B) is said pharmaceutically acceptable acid addition salt of said peptide.

7. The method of claim 5, wherein said derivative (B) is said pharmaceutically acceptable carboxylate salt of said peptide.

8. The method of claim 5, wherein said derivative (B) is said pharmaceutically acceptable lower alkyl ester of said peptide.

9. The method of claim 5, wherein said derivative (B) is said pharmaceutically acceptable amide of said peptide.

10. The method of claim 9, wherein said pharmaceutically acceptable amide of said peptide is amide.

11. The method of claim 9, wherein said pharmaceutically acceptable amide of said peptide is a lower alkyl amide.

12. The method of claim 9, wherein said pharmaceutically acceptable amide of said peptide is a lower dialkyl amide.

3. A method for stimulating insulin secretion from the pancreas in an individual in a hyperglycemic state, said method comprising

administering to said individual an effective amount of an insulinotropic molecule which is sufficient to stimulate insulin secretion in said individual, wherein said insulinotropic molecule is selected from the group consisting of:

(A) a peptide having the amino acid sequence;

His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly; and

(B) a derivative of said peptide (A), wherein said derivative is selected from the group consisting of;

(1) a pharmaceutically acceptable acid addition salt of said peptide;

(2) a pharmaceutically acceptable carboxylate salt of said peptide;

(3) a pharmaceutically acceptable lower alkyl ester of said peptide; and

(4) a pharmaceutically acceptable amide of said peptide;

wherein said molecule is substantially free of natural contaminants, and has an insulinotropic activity which exceeds the insulinotropic activity of glucagon-like peptide GLP-1 (1-36) (GLP-1 (1-36)) or glucagon-like peptide-1(1-37) (GLP-1(1-37)).

4. The method of claim 3, wherein said individual is a human.

35. The method of claim 3 wherein said administering is intravenous, intramuscular or subcutaneous administration.

13. A method for enhancing the expression of insulin in a pancreatic β

-type islet cell, said method comprising

providing to a mammalian pancreatic β

-type islet cell an effective amount of an insulinotropic molecule selected from the group consisting of;

(A) a peptide having the amino acid sequence;

His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-X, wherein X is selected from the group consisting of (a) Lys, and (b) Lys-Gly, and

(B) a derivative of said peptide (A), wherein said derivative is selected from the group consisting of;

(1) a pharmaceutically acceptable acid addition salt of said peptide;

(2) a pharmaceutically acceptable carboxylate salt of said peptide;

(3) a pharmaceutically acceptable lower alkyl ester of said peptide; and

(4) a pharmaceutically acceptable amide of said peptide;

wherein said molecule is substantially free of natural contaminants, and has an insulinotropic activity which exceeds the insulinotropic activity of glucagon-like peptide GLP-1 (1-36) (GLP-1 (1-36)) or glucagon-like peptide-1(1-37) (GLP-1(1-37)).

14. The method of claim 13, wherein said mammal is a human.

17. The method of any one of claims 13, 14, 15 or 16 wherein X is Lys.

18. The method of claim 17, wherein said insulinotropic molecule is said derivative (B) of said peptide.

19. The method of claim 18, wherein said derivative (B) is said pharmaceutically acceptable acid addition salt of said peptide.

20. The method of claim 18, wherein said derivative (B) is said pharmaceutically acceptable carboxylate salt of said peptide.

21. The method of claim 18, wherein said derivative (B) is said pharmaceutically acceptable lower alkyl ester of said peptide.

22. The method of claim 18, wherein said derivative (B) is said pharmaceutically acceptable amide of said peptide.

23. The method of claim 22, wherein said pharmaceutically acceptable amide of said peptide is amide.

24. The method of claim 22, wherein said pharmaceutically acceptable amide of said peptide is a lower alkyl amide.

25. The method of claim 22, wherein said pharmaceutically acceptable amide of said peptide is a lower dialkyl amide.

26. The method of any one of claims 13, 14, 15 or 16, wherein X is Lys-Gly.

27. The method of claim 26, wherein said insulinotropic molecule is said derivative (B) of said peptide.

28. The method of claim 26, wherein said derivative (B) is said pharmaceutically acceptable acid addition salt of said peptide.

29. The method of claim 26, wherein said derivative (B) is said pharmaceutically acceptable carboxylate salt of said peptide.

30. The method of claim 26, wherein said derivative (B) is said pharmaceutically acceptable lower alkyl ester of said peptide.

31. The method of claim 26, wherein said derivative (B) is said pharmaceutically acceptable amide of said peptide.

32. The method of claim 31, wherein said pharmaceutically acceptable amide of said peptide is amide.

33. The method of claim 31, wherein said pharmaceutically acceptable amide of said peptide is a lower alkyl amide.

34. The method of claim 31, wherein said pharmaceutically acceptable amide of said peptide is a lower dialkyl amide.

15. A method for stimulating insulin secretion from the pancreas in an individual in a hyperglycemic state, said method comprising

administering to said individual an effective amount of an insulinotropic molecule which is sufficient to stimulate insulin secretion in said individual, wherein said insulinotropic molecule is selected from the group consisting of:

His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-X, wherein X is selected from the group consisting of (a) Lys, and (b) Lys-Gly,

(A) a peptide having the amino acid sequence; and

(B) a derivative of said peptide (A), wherein said derivative is selected from the group consisting of;

(1) a pharmaceutically acceptable acid addition salt of said peptide;

(2) a pharmaceutically acceptable carboxylate salt of said peptide;

(3) a pharmaceutically acceptable lower aklyl ester of said peptide; and

(4) a pharmaceutically acceptable amide of said peptide,

wherein said molecule is substantially free of natural contaminants, and has an insulinotropic activity which exceeds the insulinotropic activity of glucagon-like peptide GLP-1 (1-36) (GLP-1 (1-36)) or glucagon-like peptide-1(1-37) (GLP-1(1-37)).

16. The method of claim 15, wherein said mammal is a human.

36. The method of claim 15 wherein said administering is intravenous, intramuscular or subcutaneous administration.

37. A molecule that is a pharmaceutically acceptable amide of a peptide having the amino acid sequence:

His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly, wherein said molecule is substantially free of natural contaminants, and has an insulinotropic activity which exceeds the insulinotropic activity of glucagon-like peptide GLP-1(1-36) (GLP-1 (1-36)) or glucagon-like peptide-1(1-37) (GLP-1(1-37)).

38. An insulinotropic composition which comprises the molecule of claim 37 in admixture with a pharmaceutically acceptable carrier.

42. An insulinotropic composition which comprises the molecule of any one of claims 37, 38, 39, 40 or 41 in admixture with a pharmaceutically acceptable carrier.

39. A molecule that is a pharmaceutically acceptable amide of a peptide having the amino acid sequence:

His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-X wherein X is selected from the group consisting of (a) Lys, and (b) Lys-Gly, wherein said molecule is substantially free of natural contaminants, and has an insulinotropic activity which exceeds the insulinotropic activity of glucagon-like peptide-1(1-36) (GLP-1(1-36)) or glucagon-like peptide-1(1-37) (GLP-1(1-37)).

40. The molecule of claim 39, wherein X is Lys.

41. The molecule of claim 39, wherein X is Lys-Gly.