GLP-1 AND METHODS FOR TREATING DIABETES

• US 20090088369A1
• Filed: 11/24/2008
• Published: 04/02/2009
• Est. Priority Date: 07/04/2002
• Status: Abandoned Application

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Steiness, Eva
• Application Number:
  US12/277,148
• Publication Number:
  US 20090088369A1
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/549 having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
• CPC Class Codes: A61K 31/64 Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
• CPC Class Codes: A61K 31/702 Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 38/31 Somatostatins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• 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 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

Abstract

The present invention relates to use of GLP-1 or a related molecule having a GLP-effect for the manufacture of a medicament for preventing or treating diabetes in a mammal. The amount and timing of administration of said medicament are subsequently reduced to produce a “drug holiday.” Practice of the invention achieves effective therapy without continuous drug exposure and without continuous presence of therapeutic levels of the drug. The invention also discloses a method of treating diabetes and related disorders in a mammal by administering glucagon like peptide (GLP-1) or a related molecule having GLP-1 like effect and thereby providing a therapeutically effective amount of endogenous insulin.

Claims

1. A method for preventing or treating diabetes in a mammal, the method comprising administering GLP-1 or a related molecule having GLP-1 effect to a mammal, and administering at least one further anti-diabetic drug to the mammal.

2. A method according to claim 1, wherein the GLP-1 related molecule is an analog of GLP-1.

3. A method according to claim 2 wherein the analog of GLP-1 is exendin-3, exendin-4 or an analog or derivative thereof.

4. A method according to claim 3 wherein the analog of GLP-1 is selected from the group consisting of:

des Ser³⁹-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

25),

des Pro³⁶-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

26),

des Ala³⁵-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

27),

des Gly³⁴-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

28),

des Ser³⁹-(Lys⁴⁰(palmitoyl))exendin-4(1-39)-Lys₇-NH₂ (SEQ ID NO;

29),

des Pro³⁶-(Lys⁴⁰(palmitoyl))exendin-4(1-39)-Lys₇-NH₂ (SEQ ID NO;

32),

des Ala³⁵-(Lys⁴ (palmitoyl))exendin-4(1-39)-Lys₇-NH₂ (SEQ ID NO;

31),

des Gly³⁴-(Lys⁴⁰(palmitoyl))exendin-4(1-39)-Lys₇-NH₂ (SEQ ID NO;

30),

Lys⁴⁰(palmitoyl)exendin-4(1-39)-Lys₇-NH₂ (SEQ ID NO;

33),

des Pro³⁶,Pro³⁷-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

34),

Lys₆-des Pro³⁶,Pro³⁷,Pro³⁸-exendin-4(1-39)-NH₂ (SEQ ID NO;

35),

Asn(Glu)₅-des Pro³⁶,Pro³⁷,Pro³⁸-exendin-4(1-39)-NH₂(SEQ ID NO;

36),

Lys₆-des Pro³⁶,Pro³⁷,Pro³⁸-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

37),

Asn(Glu)₅-des Pro³⁶,Pro³⁷,Pro³⁸-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

38), and

des Pro³⁶,Pro³⁷,Pro³⁸-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

39),

or the free acids and pharmaceutically acceptable salts thereof.

5. A method according to claim 4 wherein the analogue of GLP-1 is des Pro³⁶-exendin-4(1-39)-Lys₆-NH₂ (compound 1;

SEQ ID NO;

5).

6. A method according to claim 1 wherein the further anti-diabetic drug is insulin, an insulin analog or a pharmaceutically acceptable mixture thereof.

7. A method according to claim 6 wherein the further anti-diabetic drug is human insulin, a human insulin analog or a pharmaceutically acceptable mixture thereof.

8. A method according to claim 7 wherein the further anti-diabetic drug is a human insulin analog.

9. A method according to claim 1 wherein the anti-diabetic drug is a sulfonylurea, biguanide, thiazolidinedione, diazoxide, somatostatin, or an alpha-glucosidase inhibitor.

10. A pharmaceutical composition comprising a GLP-1 or a related molecule having GLP-1 effect and at least one further anti-diabetic drug.

11. A pharmaceutical composition according to claim 10, wherein the GLP-1 related molecule is an analog of GLP-1.

12. A pharmaceutical composition according to claim 11 wherein the analog of GLP-1 is exendin-3, exendin-4, or an analog or derivative thereof.

13. A pharmaceutical composition according to claim 12 wherein the analog of GLP-1 is selected from the group consisting of:

des Ser³⁹-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

25),

des Pro³⁶-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

26),

des Ala³⁵-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

27),

des Gly³⁴-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

28),

des Ser³⁹-(Lys⁴⁰(palmitoyl))exendin-4(1-39)-Lys₇-NH₂ (SEQ ID NO;

29),

des Pro³⁶-(Lys⁴⁰(palmitoyl))exendin-4(1-39)-Lys₇-NH₂ (SEQ ID NO;

32),

des Ala³⁵-(Lys⁴⁰(palmitoyl))exendin-4(1-39)-Lys₇-NH₂ (SEQ ID NO;

31),

des Gly³⁴-(Lys⁴⁰(palmitoyl))exendin-4(1-39)-Lys₇-NH₂ (SEQ ID NO;

30),

Lys⁴⁰(palmitoyl)exendin-4(1-39)-Lys₇-NH₂ (SEQ ID NO;

33),

des Pro³⁶,Pro³⁷-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

34),

Lys₆-des Pro³⁶,Pro³⁷,Pro³⁸-exendin-4(1-39)-NH₂ (SEQ ID NO;

35),

Asn(Glu)₅-des Pro³⁶,Pro³⁷,Pro³⁸-exendin-4(1-39)-NH₂ (SEQ ID NO;

36),

Lys₆-des Pro³⁶,Pro³⁷,Pro³⁸-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

37),

Asn(Glu)₅-des Pro³⁶,Pro³⁷,Pro³⁸-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

38), and

des Pro³⁶,Pro³⁷,Pro³⁸-exendin-4(1-39)-Lys₆-NH₂ (SEQ ID NO;

39),

or the free acids and pharmaceutically acceptable salts thereof.

14. A pharmaceutical composition according to claim 13 wherein the analog of GLP-1 is des Pro³⁶-exendin-4(1-39)-Lys₆-NH₂ (compound 1;

SEQ ID NO;

5).

15. A pharmaceutical composition according to claim 10 wherein the further anti-diabetic drug is insulin, an insulin analog, or a pharmaceutically acceptable mixture thereof.

16. A pharmaceutical composition according to claim 15 wherein the further anti-diabetic drug is human insulin, a human insulin analog, or a pharmaceutically acceptable mixture thereof.

17. A pharmaceutical composition according to claim 16 wherein the further anti-diabetic drug is a human insulin analog.

18. A pharmaceutical composition according to claim 10 wherein the anti-diabetic drug is a sulfonylurea, biguanide, thiazolidinedione, diazoxide, somatostatin, or an alpha-glucosidase inhibitor.