Method of regulating glucose metabolism, and reagents related thereto

• US 20030153509A1
• Filed: 07/03/2002
• Published: 08/14/2003
• Est. Priority Date: 02/02/1998
• Status: Active Grant

• Current Assignee: 1149336 Ontario Inc., Arisaph Pharmaceuticals, Inc., New England Medical Center Hospitals, Inc.
• Original Assignee: New England Medical Center Hospitals, Inc.
• Inventors: Bachovchin, William W., Plaut, Andrew G., Drucker, Daniel
• Granted Patent: US 6,890,898 B2
• Time in Patent Office: Days
• US Class Current: 514/19
• 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 and compositions for modification and regulation of glucose and lipid metabolism, generally to reduce insulin resistance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoprotein-emia (such as chylomicrons, VLDL and LDL), and to regulate body fat and more generally lipid stores, and, more generally, for the improvement of metabolism disorders, especially those associated with diabetes, obesity and/or atherosclerosis.

Claims

1. A method for modifying, in an animal, metabolism of glucagon-like peptide 1 (GLP-1), comprising administering to the animal a composition including one or more inhibitors of a dipeptidylpeptidase which inactivates GLP-1, which inhibitor(s) are administered in an amount sufficient to inhibit the dipeptidylpeptidase proteolysis of GLP-1.

2. A method for modifying glucose metabolism of an animal, comprising administering to the animal a composition including one or more protease inhibitors which inhibit DPIV-mediated proteolysis with a Ki of 1 nM or less.

3. A method for modifying glucose metabolism of an animal, comprising administering to the animal a composition including one or more protease inhibitors which inhibit the proteolysis of glucagon-like peptide 1 (GLP-1) and accordingly increase the plasma half-life of GLP-1.

4. A method for treating Type II diabetes, comprising administering to an animal a composition including one or more inhibitors dipeptidylpeptidase IV (DPIV).

5. The method of claim 1, wherein dipeptidylpeptidase is DPIV.

6. The method of claim 3, wherein protease inhibitor is an inhibitor of DPIV.

7. The method of claim 2 or 3, wherein administering the inhibitor reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoproteinemia.

8. The method of claim 1, 2, 3 or 4, 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.

9. The method of claim 1, 2, 3 or 4, wherein the inhibitor has an EC50 for inhibition of glucose tolerance in the nanomolar or less range

10. The method of claim 1, 2, 3 or 4, wherein the inhibitor has an EC50 for immunosuppression in the μ

M or greater range.

11. The method of claim 4, 5 or 6, wherein the inhibitor has a Ki for DPIV inhibition of 1.0 nm or less.

12. The method of claim 1, 2, 3 or 4, wherein the inhibitor is peptidomimetic of a peptide selected from the group consisting Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala.

13. The method of claim 1, 2, 3 or 4, wherein the inhibitor has a molecular weights less than 7500 amu.

14. The method of claim 1, 2, 3 or 4, wherein the inhibitor is orally active.

15. The method of claim 1, 2, 3 or 4, wherein the inhibitor is represented by the general formula;

16. The method of claim 15, wherein

W represents —

CN, —

CH═

NR₅,

R₅ represents H, an alkyl, an alkenyl, an alkynyl, —

C(X₁)(X₂)X₃, —

(CH₂)m-R₇, —

(CH₂)n-OH, —

(CH₂)n-O-alkyl, —

(CH₂)n-O-alkenyl, —

(CH₂)n-O-alkynyl, —

(CH₂)n-O—

(CH₂)m-R₇, —

(CH₂)n-SH, —

(CH₂)n-S-alkyl, —

(CH₂)n-S-alkenyl, —

(CH₂)n-S-alkynyl, —

(CH₂)n-S—

(CH₂)m-R₇, —

C(O)C(O)NH₂, —

C(O)C(O)OR′

₇;

R′

₇ represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; and

Y₁ and Y₂ can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y₁ and Y₂ are connected via a ring having from 5 to 8 atoms in the ring structure (such as pinacol or the like),

R₅₀ represents O or S;

R₅₁ represents N₃, SH₂, NH₂, NO₂ or OR′

₇;

R₅₂ represents hydrogen, a lower alkyl, an amine, OR′

₇, or a pharmaceutically acceptable salt, or R₅₁ and R₅₂ taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure

X₁ represents a halogen;

X₂ and X₃ each represent a hydrogen or a halogen

18. The method of claim 16, wherein the ring A is represented by the formula

19. The method of claim 16, wherein W represents

20. The method of claim 16, wherein R1 represents

21. The method of claim 16, wherein R2 is absent, or represents a small hydrophobic group.

22. The method of claim 16, wherein R3 is a hydrogen, or a small hydrophobic group.

23. The method of claim 16, wherein R5 is a hydrogen, or a halogentated lower alkyl.

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

25. The method of claim 16 wherein the inhibitor is represented by the general formula:

26. The method of claim 16 wherein the inhibitor is represented by the general formula

27. The method of claim 16, wherein the inhibitor is represented by the general formula:

28. The method of claim 16, wherein the inhibitor is represented by the general formula:

29. The method of claim 16, wherein the inhibitor is represented by the general formula:

30. A method for modifying, in an, animal, metabolism of peptide hormone, comprising administering to the animal a composition including one or more inhibitors of dipeptidylpeptidase IV (DPIV) in an amount sufficient to increase the plasma half-life of a peptide hormone, which peptide hormone is selected from the group consisting of glucagon-like peptide 2 (GLP-2), growth hormone-releasing factor (GHRF), vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), pituitary adenylate cyclase activating peptide (PACAP), gastric inhibitory peptide (GIP), helodermin, Peptide YY and neuropeptide Y.

31. A method for modifying glucose metabolism of an animal, comprising administering to the animal a composition including boronyl peptidomimetic of a peptide selected from the group consisting Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala.

32. The method of claim 31, wherein the boronyl peptidomimetic is represented in the general formula:

33. The method of claim 32, wherein administering the boronyl peptidomimetic reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoproteinemia.

34. The method of claim 32, wherein the boronyl peptidomimetic has an EC50 for modification of glucose metabolism which is at least one order of magnitude less than its EC50 for immunosuppression.

35. The method of claim 32, wherein the boronyl peptidomimetic has an EC50 for inhibition of glucose tolerance in the nanomolar or less range

36. The method of claim 32, wherein the boronyl peptidomimetic has an EC50 for immunosuppression in the μ

M or greater range.

37. The method of claim 32, wherein the boronyl peptidomimetic is orally active.

38. A method for modifying glucose metabolism of an animal, comprising administering to the animal a composition including boronyl inhibitor of peptidomimetic of a peptide selected from the group consisting Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala.