Methods of Regulating Glucose Metabolism, and Reagents Related Thereto

• US 20140178472A1
• Filed: 07/25/2013
• Published: 06/26/2014
• Est. Priority Date: 02/02/1998
• Status: Active Grant

• 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.
• Granted Patent: US 9,044,424 B2
• Time in Patent Office: Days
• US Class Current: 424/474
• 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

1-37. -37. (canceled)

38. 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.

39. The method of claim 38, wherein the inhibitor has a Ki for inhibition of DPIV of 1.0 nM or less.

40. The method of claim 39, wherein the inhibitor has a Ki for inhibition of DPIV of 0.1 nM or less.

41. The method of claim 40, wherein the inhibitor has a Ki for inhibition of DPIV of 0.01 nM or less.

42. The method of claim 38, wherein the inhibitor has an EC₅₀ for treatment of Type II diabetes at least one order of magnitude less than its EC₅₀ for immunosuppression.

43. The method of claim 42, wherein the inhibitor has an EC₅₀ for treatment of Type II diabetes at least two orders of magnitude less than its EC₅₀ for immunosuppression.

44. The method of claim 38, wherein the inhibitor has a molecular weight less than 5000 amu.

45. The method of claim 44, wherein the inhibitor has a molecular weight less than 2000 amu.

46. The method of claim 45, wherein the inhibitor has a molecular weight less than 1000 amu.

47. The method of claim 38, wherein the animal is a mammal.

48. The method of claim 47, wherein the mammal is a human.

49. The method of claim 38, wherein the inhibitor is administered in a solid dosage form.

50. The method of claim 49, wherein the solid dosage form is a tablet, capsule or pill.

51. The method of claim 49, wherein the solid dosage form is a tablet.

52. The method of claim 51, wherein the solid dosage form is a coated tablet.

53. The method of claim 38, wherein the duration of the therapeutic effect is about 24 hours.

54. The method of claim 38, wherein the animal is a human;

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

55. The method of claim 38, wherein the animal is a human;

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

56. The method of claim 38, wherein the animal is a human;

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

57. The method of claim 38, wherein the animal is a human;

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

58. The method of claim 38, wherein the animal is a human;

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

59. The method of claim 38, 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.

60. The method of claim 38, 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.

61. The method of claim 38, 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.

62. The method of claim 38, 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.

63. The method of claim 38, 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.

64. The method of claim 38, 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.

65. The method of claim 38, 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.

66. The method of claim 38, 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.

67. The method of claim 38, 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.