Method of regulating glucose metabolism, and reagents related thereto

• US 7,078,381 B2
• Filed: 03/04/2004
• Issued: 07/18/2006
• Est. Priority Date: 02/02/1998
• Status: Expired due to Term

• Current Assignee: 1149336 Ontario Inc., Arisaph Pharmaceuticals, Inc., New England Medical Center Hospitals, Inc.
• Original Assignee: Trustees of Tufts College
• Inventors: Bachovchin, William W., Plaut, Andrew G., Drucker, Daniel
• Primary Examiner(s): RUSSEL, JEFFREY E
• Application Number:
  US10/794,316
• Publication Number:
  US 20040176307A1
• Time in Patent Office: 866 Days
• Field of Search: 514/2, 514/18, 514/19, 514/119, 514/423, 514/626, 530/330, 530/331
• US Class Current: 514/6.7
• 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 modifying glucose metabolism and treating Type II diabetes in an animal, along with modifying metabolism of a peptide hormone in an animal. Compositions disclosed herein comprise one or more peptides and/or peptide analogs which include a functional group that reacts with an active site residue of a protease.

Claims

1. A method for modifying glucose metabolism of an animal in need of modification of glucose metabolism, comprising conjointly administering to the animal a composition comprising an inhibitor of dipeptidylpeptidase IV or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify glucose metabolism but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents.

2. A method for treating Type II diabetes in an animal in need of treatment therefor, comprising conjointly administering to the animal a composition comprising an inhibitor of dipeptidylpeptidase IV or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat Type II diabetes but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents.

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

4. The method of claim 1 or 2, 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.

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

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

M or greater range.

7. The method of claim 1 or 2, wherein the inhibitor has a K_i for DPIV inhibition of 10 nM or less.

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

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

10. The method of claim 1 or 2, wherein the inhibitor has a molecular weight less than 7500 amu.

11. The method of claim 1 or 2, wherein the inhibitor is administered orally.

12. The method of claim 1 or 2, wherein the inhibitor is represented by the general formula:

13. The method of claim 12, wherein

W represents CN, —

CH═

NR₅,

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

15. The method of claim 13, wherein W represents

16. The method of claim 13, wherein R₁ represents

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

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

19. The method of claim 12, wherein R₅ is a hydrogen, or a halogenated lower alkyl.

20. The method of claim 13, wherein X₁ is a fluorine, and X₂ and X₃, if halogens, are fluorine.

21. The method of claim 12, wherein the inhibitor is represented by the general formula:

22. The method of claim 12, wherein the inhibitor is represented by the general formula:

23. The method of claim 1 or 2, wherein the inhibitor is represented by the general formula:

24. The method of claim 13, wherein the inhibitor is represented by the general formula:

25. A method for modifying metabolism of a peptide hormone in an animal in need of modification of peptide hormone metabolism, comprising conjointly administering to the animal a composition including one or more inhibitors of dipeptidylpeptidase IV (DPIV) or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify the metabolism of a peptide hormone in the animal but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the peptide hormone is selected from 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.

26. A method for modifying glucose metabolism of an animal, comprising conjointly administering to the animal in need of modification of glucose metabolism, a composition comprising a boronyl peptidomimetic of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify the glucose metabolism of the animal but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents.

27. The method of claim 26, wherein the boronyl peptidomimetic is represented in the general formula:

28. The method of claim 27, wherein administering the boronyl peptidomimetic reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia.

29. The method of claim 27, 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.

30. The method of claim 27, wherein the boronyl peptidomimetic has an EC₅₀ for inhibition of glucose tolerance in the nanomolar or less range.

31. The method of claim 27 wherein the boronyl peptidomimetic has an EC₅₀ for inhibition of glucose tolerance of 10 nM or less.

32. The method of claim 27, wherein the boronyl peptidomimetic has an EC₅₀ for immunosuppression in the μ

M or greater range.

33. The method of claim 27, wherein the boronyl peptidomimetic is administered orally.

34. A method for modifying glucose metabolism in a glucose intolerant animal, comprising conjointly administering to the animal a composition including one or more protease inhibitors which inhibit DPIV-mediated proteolysis with a K_i in the nanomolar or less range or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify glucose metabolism but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents.

35. A method for modifying metabolism of a peptide hormone in a glucose intolerant animal, comprising conjointly administering to the animal a composition including one or more inhibitors of dipeptidylpeptidase IV (DPIV) or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents, wherein the inhibitor inhibits DPIV with a K_i in the nanomolar or less range, in an amount sufficient to increase the plasma half-life of the peptide hormone but not sufficient to suppress the immune system of the animal, which peptide hormone is selected from 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.

36. A method for modifying glucose metabolism of a glucose intolerant animal, comprising conjointly 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 or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify glucose metabolism but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents.

37. The method of claim 34, 35 or 36, wherein administering the inhibitor reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia.

38. The method of claim 34, 35 or 36, 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.

39. The method of claim 34, 35 or 36, wherein the inhibitor has an EC₅₀ for inhibition of glucose tolerance in the nanomolar or less range.

40. The method of claim 34, 35 or 36, wherein the inhibitor has an EC₅₀ for immunosuppression in the μ

M or greater range.

41. The method of any of claim 34, 35 or 36, wherein the inhibitor has a K_i for DPIV inhibition of 10 nM or less.

42. The method of claim 34, 35 or 36, wherein the inhibitor is peptidomimetic of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala.

43. The method of claim 34, 35 or 36, wherein the inhibitor has a molecular weight less than 7500 amu.

44. The method of claim 34, 35 or 36, wherein the inhibitor is administered orally.

45. The method of claim 34, 35 or 36, wherein the inhibitor is represented by the general Formula VII:

46. The method of claim 45, wherein W represents CN, —

CH═

NR₅,

47. The method of claim 45, wherein the ring A is represented by the formula

48. The method of claim 45, wherein W represents

49. The method of claim 45, wherein R₁ represents

50. The method of claim 45, wherein R₂ is absent, or represents a small hydrophobic group.

51. The method of claim 45, wherein R₃ is a hydrogen, or a small hydrophobic group.

52. The method of claim 45, wherein R₅ is a hydrogen, or a halogenated lower alkyl.

53. The method of claim 45, wherein X₁ is a fluorine, and X₂ and X₃, if halogens, are fluorine.

54. The method of claim 45, wherein the inhibitor is represented by the general formula (VIII):

55. The method of claim 45, wherein the inhibitor is represented by the general Formula IX:

56. The method of claim 45, wherein the inhibitor is represented by the general formula:

57. The method of claim 45, wherein the inhibitor is represented by the general Formula Xa or Xb:

58. A method for treating Type II diabetes in an animal in need thereof, comprising conjointly administering to the animal a composition including one or more inhibitors of a dipeptidylpeptidase or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat Type II diabetes but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the inhibitor is represented by the general Formula I:

59. The method of claim 58, wherein the ring A is represented by the formula

60. The method of claim 58, wherein W represents

61. The method of claim 58, wherein R₁ represents

62. The method of claim 58, wherein R₂ is absent, or represents a small hydrophobic group.

63. The method of claim 58, wherein R₃ is a hydrogen, or a small hydrophobic group.

64. The method of claim 58, wherein R₅ is a hydrogen, or a halogenated lower alkyl.

65. The method of claim 58, wherein X₁ is a fluorine, and X₂ and X₃, if halogens, are fluorine.

66. The method of claim 58, wherein the inhibitor is represented by the general Formula (II):

67. The method of claim 58, wherein the inhibitor is represented by the general Formula III:

68. The method of claim 58, wherein the inhibitor is represented by the general formula:

69. The method of claim 58, wherein the inhibitor is represented by the general Formula IVa or IVb:

70. The method of claim 69, wherein the ring A is represented by the formula

71. The method of claim 69, wherein R₂ is absent, or represents a small hydrophobic group.

72. The method of claim 69, wherein R₃ is a hydrogen, or a small hydrophobic group.

73. The method of claim 58, wherein the inhibitor is peptidomimetic of a peptide selected from Pro-Pro, and Ala-Pro.

74. The method of claim 58, wherein the inhibitor has an EC₅₀ for immunosuppression in the μ

M or greater range.

75. The method of claim 58, wherein the inhibitor is administered orally.

76. The method of claim 58, wherein administering the inhibitor reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia.

77. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, or 58, wherein said conjointly administering is achieved by simultaneous dosing of the individual components.

78. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, or 58, wherein said conjointly administering is achieved by sequential dosing of the individual components.

79. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, or 58, wherein said conjointly administering is achieved by separate dosing of the individual components.

80. A method of any one of claims 1, 2, 25, 27, 34, 35, 36, or 58, wherein said conjointly administering is achieved by dosing the individual components in the same composition.

81. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, or 58, further comprising administering the inhibitor or composition in conjunction with a pharmaceutically acceptable carrier.