Methods of regulating glucose metabolism, and reagents related thereto

• US 9,044,424 B2
• Filed: 07/25/2013
• Issued: 06/02/2015
• 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:
  US13/951,060
• Publication Number:
  US 20140178472A1
• Time in Patent Office: 677 Days
• Field of Search: None
• US Class Current: 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

The present invention provides methods for modification and regulation of glucose metabolism by administering to an animal a therapeutically effective amount 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 increase the plasma half-life of glucagon-like peptide 1 (GLP-1) but not sufficient to suppress the immune system of the animal.

Claims

1. A method for modifying glucose metabolism, 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 increase the plasma half-life of glucagon-like peptide 1 (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 treatment of Type II diabetes 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 treatment of Type II diabetes 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 the animal is a mammal.

11. The method of claim 10, wherein the mammal is a human.

12. The method of claim 1, wherein the inhibitor is administered in a solid dosage form.

13. The method of claim 12, wherein the solid dosage form is a tablet, capsule or pill.

14. The method of claim 12, wherein the solid dosage form is a tablet.

15. The method of claim 14, wherein the solid dosage form is a coated tablet.

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

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

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

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

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

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

and the inhibitor is administered in the form of a tablet, capsule or pill.

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

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

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

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

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

the inhibitor is administered in the form of a tablet, capsule or pill; and

the inhibitor has a molecular weight less than 1000 amu.

23. The method of claim 1, wherein 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.

24. The method of claim 1, wherein 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.

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

the inhibitor is administered in the form of a tablet, capsule or pill; and

the duration of the therapeutic effect is about 24 hours.

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

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

the duration of the therapeutic effect is about 24 hours.

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

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

the duration of the therapeutic effect is about 24 hours.

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

the inhibitor is administered in the form of a tablet, capsule or pill;

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

the inhibitor has a molecular weight less than 1000 amu.

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

the inhibitor is administered in the form of a tablet;

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

the inhibitor has a molecular weight less than 1000 amu.

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

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

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

the inhibitor has a molecular weight less than 1000 amu.