Modified exendins and exendin agonists

• US 20050267034A1
• Filed: 06/30/2005
• Published: 12/01/2005
• Est. Priority Date: 04/30/1999
• Status: Active Grant

• Current Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Young, Andrew A., Prickett, Kathryn S.
• Granted Patent: US 8,057,822 B2
• Time in Patent Office: Days
• US Class Current: 514/4.900
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• 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 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

Novel modified exendins and exendin agonists having an exendin or exendin agonist linked to one or more polyethylene glycol polymers, for example, and related formulations and dosages and methods of administration thereof are provided. These modified exendins and exendin agonists, compositions and methods are useful in treating diabetes and conditions that would be benefited by lowering plasma glucose or delaying and/or slowing gastric emptying or inhibiting food intake.

Claims

1-35. -35. (canceled)

36. A modified exendin or agonist analog of an exendin comprising an exendin or agonist analog of an exendin linked to one or more molecular weight increasing compounds.

37. The modified exendin or agonist analog of an exendin of claim 36, wherein said exendin or agonist analog of an exendin is exendin-4.

38. The modified exendin or agonist analog of an exendin of claim 36, wherein said exendin or agonist analog of an exendin is linked to one molecular weight increasing compound.

39. The modified exendin or agonist analog of an exendin of claim 36, wherein said exendin or agonist analog of an exendin is linked to two molecular weight increasing compounds.

40. The modified exendin or agonist analog of an exendin of claim 39, wherein said molecular weight increasing compounds are the same or different.

41. The modified exendin or agonist analog of an exendin of claim 36, wherein said exendin or agonist analog of an exendin is linked to three molecular weight increasing compounds.

42. The modified exendin or agonist analog of an exendin of claim 41, wherein at least one of said molecular weight increasing compounds is different from the remaining molecular weight increasing compounds.

43. The modified exendin or agonist analog of an exendin of claim 36, wherein said one or more molecular weight increasing compounds each have molecular weights between 500 and 20,000.

44. The modified exendin or agonist analog of an exendin of claim 36, wherein said exendin or agonist analog of an exendin is linked to said one or more molecular weight increasing compounds through an epsilon amino group on a lysine amino acid of said exendin or agonist analog of an exendin.

45. The modified exendin or agonist analog of an exendin of claim 36, wherein said modified exendin or agonist analog of an exendin comprises an amino acid sequence according to SEQ ID NOs:

212, 223, 226 or 235.

46. The modified exendin or agonist analog of an exendin of claim 36, wherein said modified exendin or agonist analog of an exendin comprises the amino acid sequence of SEQ ID NO:

223.

47. The modified exendin or agonist analog of an exendin of claim 36, wherein said modified exendin or agonist analog of an exendin comprises the amino acid sequence of SEQ ID NO:

212.

48. The modified exendin or agonist analog of an exendin of claim 36, wherein said modified exendin or agonist analog of an exendin comprises the amino acid sequence of SEQ ID NO:

226.

49. The modified exendin or agonist analog of an exendin of claim 36, wherein said exendin or agonist analog of an exendin is linked to one or more molecular weight increasing compounds at an amino, carboxyl, or thiol group of said exendin or exendin agonist.

50. The modified exendin or agonist analog of an exendin of claim 36, wherein said one or more molecular weight increasing compounds are linked to the N or C terminal residue, or the N and C termini of side chains of one or more amino acids of said exendin or agonist analog of an exendin, wherein said amino acids are selected from the group consisting of lysine, aspartic acid, glutamic acid, and cysteine.

51. The modified exendin or agonist analog of an exendin of claim 36, wherein said one or more molecular weight increasing compounds are linked to said exendin or agonist analog of an exendin at one or more amino acid side chain moieties with amine or carboxylic groups, or at one or more amine or carboxylic groups.

52. A pharmaceutical composition comprising a modified exendin or agonist analog of an exendin of claim 36 and a pharmaceutically acceptable carrier.

53. A method for reducing appetite of a subject comprising administering to said subject an amount of the exendin or agonist analog of an exendin of claim 36 effective to reduce appetite in said subject.

54. A method for lowering plasma lipids in a subject comprising administering to said subject an amount of the exendin or agonist analog of an exendin of claim 36 effective to lower plasma lipids in said subject.

55. A method for reducing weight in a subject comprising administering to said subject an amount of the exendin or agonist analog of an exendin of claim 36 effective to cause a reduction of weight in said subject.

56. A method or modulating triglyceride levels in a subject comprising administering to said subject an amount of the exendin or agonist analog of an exendin of claim 36 effective to modulate triglyceride levels in said subject.

57. A method for suppressing glucagon secretion in a subject comprising comprising administering to said subject an amount of the exendin or agonist analog of an exendin of claim 36 effective to suppress glucagon secretion in said subject.

58. A method for treating diabetes mellitus in a subject comprising administering to said subject an amount of the exendin or agonist analog of an exendin of claim 36 effective to normalize blood glucose in said subject.