Method of regulating glucose metabolism, and reagents related thereto

• US 8,318,669 B2
• Filed: 11/09/2010
• Issued: 11/27/2012
• 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 J.
• Primary Examiner(s): Russel, Jeffrey E
• Application Number:
  US12/942,313
• Publication Number:
  US 20110172149A1
• Time in Patent Office: 749 Days
• Field of Search: None
• US Class Current: 514/7.2
• 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

The present invention provides methods for modification and regulation of glucagon-like peptide 1 (GLP-1) metabolism by administering therapeutically effective amounts of an inhibitor of dipeptidylpeptidase IV (DPIV) or a pharmaceutically acceptable salt thereof, where the inhibitor has a Ki for inhibition of DPIV of 10 nM or less; and the inhibitor is administered in an amount sufficient to inhibit DPIV proteolysis of GLP-1 but not sufficient to suppress the immune system of the animal.

Claims

1. A method for modifying metabolism of glucagon-like peptide 1 (GLP-1), comprising administering orally to an animal in need thereof a therapeutically effective amount of an inhibitor of dipeptidylpeptidase IV (DPIV) or a pharmaceutically acceptable salt thereof once daily, wherein the inhibitor has a Ki for inhibition of DPIV of 10 nM or less;

the duration of the therapeutic effect is at least about 24 hours; and

the inhibitor is administered in an amount sufficient to inhibit DPIV proteolysis of GLP-1 but not sufficient to suppress the immune system of the animal.

2. The method of claim 1, wherein the inhibitor has a Ki for inhibition of DPIV of 1.0 nM or less.

3. The method of claim 2, wherein the inhibitor has a Ki for inhibition of DPIV of 0.1 nM or less.

4. The method of claim 3, wherein the inhibitor has a Ki for inhibition of DPIV of 0.01 nM or less.

5. The method of claim 1, wherein the inhibitor has an EC₅₀ for modification of GLP-1 metabolism at least one order of magnitude less than its EC₅₀ for immunosuppression.

6. The method of claim 5, wherein the inhibitor has an EC₅₀ for modification of GLP-1 metabolism at least two orders of magnitude less than its EC₅₀ for immunosuppression.

7. The method of claim 1, wherein the inhibitor has a molecular weight less than 5000 amu.

8. The method of claim 7, wherein the inhibitor has a molecular weight less than 2000 amu.

9. The method of claim 8, wherein the inhibitor has a molecular weight less than 1000 amu.

10. The method of claim 1, wherein said inhibition of DPIV proteolysis of GLP-1 treats Type II diabetes.

11. The method of claim 1, wherein the duration of the therapeutic effect is about 24 hours.

12. The method of claim 1, wherein the animal is a human.

13. The method of claim 1, wherein the inhibitor is administered in the form of a tablet.

14. The method of claim 1, wherein the inhibitor is administered in the form of a coated tablet.

15. The method of claim 1, wherein the animal is a human;

and the duration of the therapeutic effect is about 24 hours.

16. The method of claim 1, wherein the animal is a human;

and the inhibitor has a molecular weight less than 1000 amu.

17. The method of claim 1, wherein the animal is a human;

and the inhibitor is administered in the form of a tablet.

18. The method of claim 1, wherein the animal is a human;

and the inhibitor is administered in the form of a coated tablet.

19. The method of claim 1, wherein the inhibitor has a molecular weight less than 1000 amu;

and the duration of the therapeutic effect is about 24 hours.

20. The method of claim 1, wherein the inhibitor has a molecular weight less than 1000 amu;

and the inhibitor is administered in the form of a tablet.

21. The method of claim 1, wherein the inhibitor has a molecular weight less than 1000 amu;

and the inhibitor is administered in the form of a coated tablet.

22. The method of claim 1, wherein the duration of the therapeutic effect is about 24 hours;

the animal is a human; and

the inhibitor is administered in the form of a tablet.

23. The method of claim 1, wherein the duration of the therapeutic effect is about 24 hours;

the animal is a human; and

the inhibitor is administered in the form of a coated tablet.

24. The method of claim 1, wherein the duration of the therapeutic effect is about 24 hours;

the animal is a human;

the inhibitor is administered in the form of a tablet; and

the inhibitor has a molecular weight less than 1000 amu.

25. The method of claim 1, wherein the duration of the therapeutic effect is about 24 hours;

the animal is a human;

the inhibitor is administered in the form of a coated tablet; and

the inhibitor has a molecular weight less than 1000 amu.

26. The method of claim 1, wherein the duration of the therapeutic effect is about 24 hours;

the animal is a human;

the inhibitor is administered in the form of a tablet;

the inhibitor has a molecular weight less than 1000 amu; and

said inhibition of DPIV proteolysis of GLP-1 treats Type II diabetes.

27. The method of claim 1, wherein the duration of the therapeutic effect is about 24 hours;

the animal is a human;

the inhibitor is administered in the form of a coated tablet;

the inhibitor has a molecular weight less than 1000 amu; and

said inhibition of DPIV proteolysis of GLP-1 treats Type II diabetes.