Insulinotropic hormone and uses thereof

• US 6,849,708 B1
• Filed: 08/10/2000
• Issued: 02/01/2005
• Est. Priority Date: 05/05/1986
• Status: Expired due to Fees

• 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:
  US09/635,679
• Time in Patent Office: 1,636 Days
• Field of Search: 514/2, 514/12, 514/866, 514/3, 514/4, 514/100, 530/324, 530/300, 530/303, 530/308, 530/350
• US Class Current: 530/308
• 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 derivative of glucagon-like peptide-1 (7-37), (GLP-I (7-37)), wherein the amino acid sequence of said derivative has the same number of amino acids as said GLP-I (7-37), and at least 80% amino acid identity to said GLP-I (7-37), and wherein said derivative has an insulinotropic activity that exceeds the insulinotropic activity of GLP-I (1-37) and GLP-I (1-36).

2. The derivative of claim 1, wherein said derivative has at least 90% amino acid identity to said GLP-I (7-37).

3. The derivative of claim 1, wherein said derivative has at least 95% amino acid identity to said GLP-I (7-37).

8. The derivative of claim 1, said derivative having the formula:

(1) H₂N—

X—

CO—

R¹

wherein R¹ is OH, OM, or —

NR²R³;

M is a pharmaceutically acceptable cation or a lower branched or unbranched alkyl group;

R² and R³ are the same or different and selected from the group consisting of hydrogen and a lower branched or unbranched alkyl group;

X is a derivative of glucagon-like peptide-1 (7-37), (GLP-1 (7-37)), wherein the amino acid sequence of said derivative has the same number of amino acids as said GLP-1 (7-37), and has at least 80% amino acid identity to said GLP-1 (7-37);

NH₂ is the amine group of the amino terminus of X;

CO is the carbonyl group of the carboxy terminus of X;

(2) the acid addition salts of (1);

(3) the amino or carboxyl protected form of (1);

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

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

or

(6) a pharmaceutically acceptable amide of said peptide;

wherein said derivative has an insulinotropic activity that exceeds the insulinotropic activity of GLP-1 (1-37) and GLP-1 (1-36).

9. The derivative of claim 8, wherein said derivative has at least 90% amino acid identity to said GLP-1 (7-37).

10. The derivative of claim 8, wherein said derivative has at least 95% amino acid identity to said GLP-1 (7-37).

4. A derivative of glucagon-like peptide-1 (7-37), (GLP-I (7-37)), wherein the amino acid sequence of said derivative has the same number of amino acids as said GLP-I (7-37), and an insulinotropic activity that exceeds the insulinotropic activity of GLP-I (1-37) and GLP-I (1-36), and wherein the amino acid sequence of said derivative is that of GLP-I (7-37) except that an amino acid residue has been substituted with a different amino acid residue.

5. The derivative of claim 4, wherein a hydrophobic amino acid residue of GLP-I (7-37) has been substituted with a different hydrophobic amino acid residue.

6. The derivative of claim 4, wherein a basic amino acid residue of GLP-1 (7-37) has been substituted with a different basic amino acid residue.

7. The derivative of claim 4, wherein an aromatic amino acid residue of GLP-1 (7-37) has been substituted with a different aromatic amino acid residue.

11. The derivative of claim 4, said derivative having the formula:

(1) H₂N—

X—

CO—

R¹

wherein R¹ is OH, OM, or —

NR²R³;

M is a pharmaceutically acceptable cation or a lower branched or unbranched alkyl group;

R² and R³ are the same or different and selected from the group consisting of hydrogen and a lower branched or unbranched alkyl group;

X is a derivative of glucagon-like peptide-1 (7-37), (GLP-1 (7-37)), wherein the amino acid sequence of said derivative is that of GLP-1 (7-37) except that an amino acid residue has been substituted with a different amino acid residue;

NH₂ is the amine group of the amino terminus of X;

CO is the carbonyl group of the carboxy terminus of X;

(2) the acid addition salts of (1);

(3) the amino or carboxyl protected form of (1);

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

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

or

(6) a pharmaceutically acceptable amide of said peptide;

wherein said derivative has an insulinotropic activity that exceeds the insulinotropic activity of GLP-1 (1-37) and GLP-1 (1-36).

12. The derivative of claim 11, wherein a hydrophobic amino acid residue of GLP-1 (7-37) has been substituted with a different hydrophobic amino acid residue.

13. The derivative of claim 11, wherein a basic amino acid residue of GLP-1 (7-37) has been substituted with a different basic amino acid residue.

14. The derivative of claim 11, wherein an aromatic amino acid residue of GLP-1 (7-37) has been substituted with a different aromatic amino acid residue.

15. A compound which is:

(A) a peptide having at least 80% homology with glucagon-like peptide-1 (7-37) (GLP-I (7-37)), with the proviso that the peptide is not GLP-I (7-34), GLP-I (7-35), GLP-I (7-36) or GLP-I (7-37);

or

(B) a peptide which is

(i) a pharmaceutically acceptable acid addition salt of (A);

(ii) a pharmaceutically acceptable carboxylate salt of (A);

(iii) a pharmaceutically acceptable lower alkyl ester of (A);

or

(iv) a pharmaceutically acceptable amide, alkyl amide or dialkyl amide of (i), (ii), or (iii);

wherein the compound is substantially free of natural contaminants, and has an insulinotropic activity which exceeds the insulinotropic activity of GLP-I (1-36) or GLP-1 (1-37).

16. A compound according to claim 15 having an insulinotropic activity at a concentration of at least 10⁻

11 M.

17. A compound according to claim 15, having an insulinotropic activity at a concentration of at least 10⁻

10 M.

18. An insulinotropic medicament comprising an insulinotropically effective amount of a compound according to claim 15 in combination with a pharmaceutically acceptable carrier.

19. A compound which is:

(A) a peptide having at least 80% homology with glucagon-like peptide-1 (7-36) (GLP-I (7-36)), with the proviso that the peptide is not GLP-I (7-34), GLP-I (7-35), GLP-I (7-36) or GLP-I (7-37);

or

(B) a peptide which is

(i) a pharmaceutically acceptable acid addition salt of (A);

(ii) a pharmaceutically acceptable carboxylate salt of (A);

(iii) a pharmaceutically acceptable lower alkyl ester of (A);

or

(iv) a pharmaceutically acceptable amide, alkyl amide or dialkyl amide of (i), (ii), or (iii);

wherein the compound is substantially free of natural contaminants, and has an insulinotropic activity which exceeds the insulinotropic activity of GLP-I (1-36) or GLP-I (1-37).

20. A compound according to claim 19 having an insulinotropic activity at a concentration of at least 10⁻

11 M.

21. A compound according to claim 19, having an insulinotropic activity at a concentration of at least 10⁻

10 M.

22. An insulinotropic medicament comprising an insulinotropically effective amount of a compound according to claim 19 in combination with a pharmaceutically acceptable carrier.

23. A compound which is:

(A) a peptide having at least 80% homology with glucagon-like peptide-1 (7-35) (GLP-I (7-35)) or glucagon-like peptide-1 (7-34) (GLP-I (7-34), with the proviso that the peptide is not GLP-I (7-34), GLP-I (7-35), GLP-I (7-36) or GLP-I (7-37);

or

(B) a peptide which is

(i) a pharmaceutically acceptable acid addition salt of (A);

(ii) a pharmaceutically acceptable carboxylate salt of (A);

(iii) a pharmaceutically acceptable lower alkyl ester of (A);

or

(iv) a pharmaceutically acceptable amide, alkyl amide or dialkyl amide of (i), (ii), or (iii);

wherein the compound is substantially free of natural contaminants, and has an insulinotropic activity which exceeds the insulinotropic activity of GLP-I (1-36) or GLP-1 (1-37).

24. A compound according to claim 23 having an insulinotropic activity at a concentration of at least 10⁻

11 M.

25. A compound according to claim 23, having an insulinotropic activity at a concentration of at least 10⁻

10 M.

26. An insulinotropic medicament comprising an insulinotropically effective amount of a compound according to claim 23 in combination with a pharmaceutically acceptable carrier.