Method of regulating glucose metabolism, and reagents related thereto

• US 7,459,428 B2
• Filed: 07/17/2006
• Issued: 12/02/2008
• Est. Priority Date: 02/02/1998
• Status: Expired due to Fees

• Current Assignee: 1149336 Ontario Inc., Arisaph Pharmaceuticals, Inc., New England Medical Center Hospitals, Inc., Trustees of Tufts College
• Original Assignee: 1149336 Ontario Inc., New England Medical Center Hospitals, Inc., Trustees of Tufts College
• Inventors: Bachovchin, William W., Plaut, Andrew G., Drucker, Daniel
• Primary Examiner(s): Russel; Jeffrey E
• Application Number:
  US11/487,947
• Publication Number:
  US 20070129314A1
• Time in Patent Office: 869 Days
• Field of Search: None
• US Class Current: 514/1.1
• 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 31/00 Medicinal preparations containing organic active ingredients
• 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 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/69 Boron compounds
• 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 38/005 Enzyme inhibitors protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 38/55 Protease inhibitors
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• 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
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid

Abstract

One aspect of the present invention relates to a method for treating Type II diabetes in an animal, comprising conjointly administering to the animal metformin and an inhibitor of dipeptidylpeptidase IV or a pharmaceutically acceptable salt thereof in an amount sufficient to treat Type II diabetes of the animal.

Claims

1. A method for treating Type II diabetes in an animal, comprising conjointly administering to the animal metformin and an inhibitor of dipeptidylpeptidase IV or a pharmaceutically acceptable salt thereof in an amount sufficient to treat Type II diabetes, wherein the amount of said inhibitor of dipeptidylpeptidase IV or pharmaceutically acceptable salt thereof is not sufficient to suppress the immune system of the animal.

2. The method of claim 1, wherein the inhibitor reduces insulin resistance, glucose intolerance, hyperglycemia, or hyperinsulinemia.

3. The method of claim 1, wherein the inhibitor has an EC₅₀ for modification of glucose metabolism which is at least one order of magnitude less than its EC₅₀ for immunosuppression.

4. The method of claim 1, wherein the inhibitor has a K_i for dipeptidylpeptidase IV inhibition of 10 nM or less.

5. The method of claim 1, wherein the inhibitor has a K_i for dipeptidylpeptidase IV inhibition of 1.0 nM or less.

6. The method of claim 1, wherein the inhibitor has a molecular weight less than 7500 amu.

7. The method of claim 1, wherein the inhibitor is administered orally.

8. The method of claim 1, wherein the inhibitor is a peptidomimetic of a peptide selected from the group consisting of Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala.

9. The method of claim 1, wherein the inhibitor is represented by Formula I:

10. The method of claim 9, wherein the ring A is represented by the formula:

11. The method of claim 9, wherein W represent

12. The method of claim 9, wherein R₁ represents

13. The method of claim 9, wherein R₂ is absent.

14. The method of claim 9, wherein R₃ is a hydrogen.

15. The method of claim 9, wherein R₅ is a hydrogen.

16. The method of claim 9, wherein X₁ is a fluorine, and X₂ and X₃, if halogens, are fluorine.

17. The method of claim 9, wherein the inhibitor is represented by Formula (II):

18. The method of claim 9, wherein the inhibitor is represented by Formula III:

19. The method of claim 1, wherein the inhibitor is represented by the Formula IV:

20. The method of claim 9, wherein the inhibitor is represented by the Formula Xa or Xb:

21. The method of claim 1, wherein said conjointly administering is achieved by simultaneous dosing of the individual components.

22. The method of claim 1, wherein said conjointly administering is achieved by sequential dosing of the individual components.

23. The method of claim 1, wherein said conjointly administering is achieved by separate dosing of the individual components.

24. The method of claim 1, wherein said conjointly administering is achieved by dosing the individual components in the same composition.