Method of regulating glucose metabolism, and reagents related thereto

• US 7,157,429 B1
• Filed: 07/28/2000
• Issued: 01/02/2007
• Est. Priority Date: 02/02/1998
• Status: Expired due to Term

• Current Assignee: Arisaph Pharmaceuticals, Inc., Daniel Drucker, New England Medical Center Hospitals, Inc.
• Original Assignee: Trustees of Tufts College
• Inventors: Plaut, Andrew G., Drucker, Daniel, Bachovchin, William A.
• Primary Examiner(s): RUSSEL, JEFFREY E
• Application Number:
  US09/628,225
• Time in Patent Office: 2,349 Days
• Field of Search: 514/2, 514/18, 514/19, 514/119, 514/423, 514/626, 530/330, 530/331, 530/300
• US Class Current: 514/5.9
• 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, hyperlipoproteinemia (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. The compositions of the present invention include dipeptidylpeptidase inhibitors, which are able to inhibit the proteolysis of GLP-1 and accordingly increase the plasma half-life of that hormone. The subject inhibitors may be peptidyl, peptidomimetic (e.g. boronyl peptidomimetics), or non-peptidyl nitrogen containing heterocycles.

Claims

1. A method for modifying glucose metabolism in a glucose intolerant animal, comprising administering to the animal, in a single daily oral dosage, a composition including one or more di-, tri- or tetra-peptidyl boronate or di-, tri- or tetra-peptidomimetic boronate protease inhibitors, wherein the boronate replaces the C-terminal carboxylate moiety, which inhibit DPIV-mediated proteolysis with a Ki of less than about 10 nM in an amount sufficient to modify glucose metabolism but not sufficient to suppress the immune system of the animal.

2. A method for modifying glucose metabolism in a glucose intolerant animal, comprising administering to the animal, in a single daily oral dosage, a composition including one or more di-, tri- or tetra-peptidyl boronate or di-, tri- or tetra-peptidomimetic boronate protease inhibitors, wherein the boronate replaces the C-terminal carboxylate moiety, which inhibit the proteolysis of glucagon-like peptide 1 (GLP-1) with a Ki of less than about 10 nM in an amount sufficient to modify glucose metabolism but not sufficient to suppress the immune system of the animal.

3. A method for modifying metabolism of a peptide hormone in a glucose intolerant animal, comprising administering to the animal a composition, in a single daily oral dosage, including one or more di-, tri- or tetra-peptidyl boronate or di-, tri- or tetra-peptidomimetic boronate inhibitors of dipeptidylpeptidase IV (DPIV), wherein the boronate replaces the C-terminal carboxylate moiety and wherein the inhibitor inhibits DPIV with a Ki of less than about 10 nM, in an amount sufficient to increase the plasma half-life of the peptide hormone, which peptide hormone is selected from 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, wherein the composition is administered in an amount sufficient to modify the metabolism of the peptide hormone but not sufficient to suppress the immune system of the animal.

4. A method for modifying glucose metabolism of a glucose intolerant animal, comprising administering to the animal a composition including a boronyl peptidomimetic inhibitor of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala in an amount sufficient to modify glucose metabolism but not sufficient to suppress the immune system of the animal.

5. The method of any one of claims 1, 2, 3, or 4, wherein administering the inhibitor reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia.

6. The method of any one of claims 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.

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

8. The method of any one of claims 1, 2, 3, or 4, wherein the inhibitor has an EC50 for immunosuppression in the μ

M or greater range.

9. The method of any one of claims 1, 2, 3, or 4, wherein the inhibitor has a Ki for DPIV inhibition of 0.5 nM or less.

10. The method of any one of claims 1, 2, or 3, wherein the inhibitor is peptidomimetic of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala.

11. The method of any one of claims 1, 2, 3, or 4, wherein the inhibitor has a molecular weight of less than 7500 amu.

12. The method of claim 4, wherein the inhibitor is administered orally.

13. The method of any one of claims 1, 2, 3, or 4, wherein the inhibitor is represented by the general Formula VII:

14. The method of claim 13, wherein the ring A is represented by the formula

15. The method of claim 13, wherein R₁ represents

16. The method of claim 13, wherein R₂ is absent, or represents a small hydrophobic group.

17. The method of claim 13, wherein R₃ is a hydrogen, or a small hydrophobic group.

18. The method of claim 13, wherein the inhibitor is represented by the general Formula (VIII):

19. The method of claim 13, wherein the inhibitor is represented by the general Formula Xa or Xb:

20. The method of any one of claims 1, 2, or 3, wherein the inhibitor is represented by the general Formula XI:

21. The method of any one of claims 1–

3, wherein the total dosage is less than 2000 mg.