Insulinotropic hormone derivatives and uses thereof

• US 7,138,486 B2
• Filed: 06/21/2004
• Issued: 11/21/2006
• 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., Mojsov, Svetlana
• Primary Examiner(s): MINNIFIELD, NITA M
• Application Number:
  US10/871,709
• Publication Number:
  US 20050119178A1
• Time in Patent Office: 883 Days
• Field of Search: 514/2, 514/3, 514/4, 514/12, 514/866, 514/100, 530/300, 530/303, 530/308, 530/324
• 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 (7-37) have been found to have insulinotropic activity. The invention pertains to a composition comprising an acid addition salt of GLP-I (7-37) and to a composition comprising a carboxylate salt of GLP-I (7-37). The invention also pertains to method of treating type II diabetes mellitus by providing derivatives of GLP-I (7-37) to the patient.

Claims

1. A composition comprising an acid addition salt of GLP-I (7-37).

2. A composition comprising a carboxylate salt of GLP-I (7-37).

3. A method for treating type II diabetes mellitus in a patient in need of such treatment, said method comprising providing to a patient in an amount sufficient to treat said diabetes 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 at least 80% amino acid identity to said GLP-1 (7-3 7), and wherein said derivative has an insulinotropic activity that exceeds the insulinotropic activity of GLP-1 (1-37) and GLP-1 (1-36).

4. The method of claim 3, wherein said derivative has at least 90% amino acid identity to said GLP-1 (7-37).

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

6. The method of claim 3, wherein said derivative has 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 are 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).

7. The method of claim 6, wherein said derivative has at least 90% amino acid identity to said GLP-1 (7-37).

8. The method of claim 6, wherein said derivative has at least 95% amino acid identity to said GLP-1 (7-37).

9. A method for treating type II diabetes mellitus in a patient in need of such treatment, said method comprising providing to a patient in an amount sufficient to treat said diabetes 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 an insulinotropic activity that exceeds the insulinotropic activity of GLP-1 (1-37) and GLP-1 (1-36), and wherein the amino acid sequence of said derivative is that of GLP-1 (7-3 7) except that an amino acid residue has been substituted with a different amino acid residue.

10. The method of claim 9, wherein a hydrophobic amino acid residue of GLP-1 (7-37) has been substituted with a different hydrophobic amino acid residue.

11. The method of claim 9, wherein a basic amino acid residue of GLP-1 (7-37) has been substituted with a different basic amino acid residue.

12. The method of claim 9, wherein an aromatic amino acid residue of GLP-1 (7-37) has been substituted with a different aromatic amino acid residue.

13. The method of claim 9, wherein said derivative has 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 are 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).

14. The method of claim 13, wherein a hydrophobic amino acid residue of GLP-1 (7-37) has been substituted with a different hydrophobic amino acid residue.

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

16. The method of claim 13, wherein an aromatic amino acid residue of GLP-1 (7-3 7) has been substituted with a different aromatic amino acid residue.

17. A method for treating type II diabetes mellitus in a patient in need of such treatment, said method comprising providing to a patient in an amount sufficient to treat said diabetes a compound which is:

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

18. The method according to claim 17 having an insulinotropic activity at a concentration of at least 10⁻

11 M.

19. The method according to claim 17, having an insulinotropic activity at a concentration of at least 10⁻

10 M.

20. The method according to claim 17, wherein said compound is in combination with a pharmaceutically acceptable carrier.