Modified exendins and exendin agonists

• US 8,951,962 B2
• Filed: 05/17/2013
• Issued: 02/10/2015
• Est. Priority Date: 04/30/1999
• Status: Expired due to Fees

• Current Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC), Amylin Pharmaceuticals LLC (Bristol-Myers Squibb Company)
• Original Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC), Amylin Pharmaceuticals LLC (Bristol-Myers Squibb Company)
• Inventors: Young, Andrew A., Prickett, Karthryn S.
• Primary Examiner(s): Rao, Manjunath
• Assistant Examiner(s): LIU, SAMUEL W
• Application Number:
  US13/896,937
• Publication Number:
  US 20140038891A1
• Time in Patent Office: 634 Days
• US Class Current: 514/3.2
• 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. A compound comprising exendin-4, or agonist analog of exendin-4, linked to a polyamino acid through the C-terminal amino acid of the exendin-4 or agonist analog of exendin-4, wherein the agonist analog of exendin-4 comprises one or more naturally occurring amino acids deleted or replaced with another amino acid or amino acids and said polyamino acid is selected from the group consisting of poly(L-lysine), poly-glutamic acid, and poly-aspartic acid.

2. The compound according to claim 1, wherein the polyamino acid is poly(L-lysine).

3. A pharmaceutical composition comprising the exendin-4, or agonist analog of exendin-4 according to claim 1 and a pharmaceutically acceptable carrier wherein the exendin-4, or the agonist analog of exendin-4 has a kidney clearance that is less than 50% of the kidney clearance of the exendin-4, or the agonist analog of exendin-4 without the C-terminal linked polyamino acid.

7. A method for treating diabetes, postprandial hyperglycemia, or impaired glucose tolerance comprising administering to a human in need of treatment for diabetes, postprandial hyperglycemia, or impaired glucose tolerance a therapeutically effective amount of a composition according to claim 3.

8. The method for treating diabetes according to claim 7.

9. The method according to claim 8, wherein the diabetes is type II diabetes.

4. A compound comprising an agonist analog of exendin-4, wherein said agonist analog of exendin-4 is linked to a polyamino acid through the C-terminal amino acid of said agonist analog of exendin-4;

and the polyamino acid is selected from the group consisting of poly(L-lysine), polyglutamic acid, and poly-aspartic acid; and

comprises the amino acid sequence of SEQ ID NO;

200, said sequence comprising;

Xaa₁ Xaa₂ Xaa₃ Gly Xaa₅ Xaa₆ Xaa₇ Xaa₈ Xaa₉ Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Xaa₁₄ Xaa_{15 Xaa16} Xaa₁₇ Ala Xaa₁₉ Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄ Xaa₂₅ Xaa₂₆ Xaa₂₇ Xaa₂₈-Z1;

wherein;

Xaa₁ is His, Arg, Tyr, Ala, Norval, Val or Norleu;

Xaa₂ is Ser, Gly, Ala or Thr;

Xaa₃ is Asp or Glu;

Xaa₅ is Ala or Thr;

Xaa₆ is Phe, Tyr or naphthylalanine;

Xaa₇ is Thr or Ser;

Xaa₈ is Ala, Ser or Thr;

Xaa₉ is Asp or Glu;

Xaa₁₀ is Ala, Leu, Ile, Val, pentylglycine or Met;

Xaa₁₁ is Ala or Ser;

Xaa₁₂ is Ala or Lys;

Xaa₁₃ is Ala or Gln;

Xaa₁₄ is Ala, Leu, Ile, pentylglycine, Val or Met;

Xaa₁₅ is Ala or Glu;

Xaa₁₆ is Ala or Glu;

Xaa₁₇ , is Ala or Glu;

Xaa₁₉ is Ala or Val;

Xaa₂₀ is Ala or Arg;

Xaa₂₁ is Ala or Leu;

Xaa₂₂ is Phe, Tyr or naphthylalanine;

Xaa₂₃ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met;

Xaa₂₄ is Ala, Glu or Asp;

Xaa₂₅ is Ala, Trp, Phe, Tyr or naphthylalanine;

Xaa₂₆ is Ala or Leu;

Xaa₂₇ is Ala or Lys;

Xaa₂₈ is Ala or Asn;

Z₁ is —

OH,

—

NH₂,

Gly Gly-Z₂,

Gly Gly Xaa₃₁-Z₂,

Gly Gly Xaa₃₁ Ser-Z₂ [SEQ ID NO;

241],

Gly Gly Xaa₃₁ Ser Ser-Z₂ [SEQ ID NO;

242],

Gly Gly Xaa₃₁ Ser Ser Gly-Z₂ [SEQ ID NO;

243],

Gly Gly Xaa₃₁ Ser Ser Gly Ala-Z₂ [SEQ ID NO;

253],

Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂ [SEQ ID NO;

254],

Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇-Z₂ [SEQ ID NO;

245],

Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈-Z₂ [SEQ ID NO;

256], or

Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈ Xaa₃₉-Z₂ [SEQ ID NO;

251] consensus disclosed as [SEQ ID NO;

203] wherein;

Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently;

Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; and

;

Z₂ is —

OH or —

NH₂;

provided that no more than three of Xaa₃, Xaa₄, Xaa₅, Xaa₆, Xaa₈, Xaa₉, Xaa₁₀, Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀, Xaa₂₁, Xaa₂₄, Xaa₂₅, Xaa₂₆, Xaa₂₇ and Xaa₂₈ are Ala; and

provided also that, if Xaa₁ is His, Arg or Tyr, then at least one of Xaa₃, Xaa₄ and Xaa₉ is Ala; and

Xaa₃₉ is Ser or Tyr.

5. The compound according to claim 4, wherein the polyamino acid is poly(L-lysine).

6. A pharmaceutical composition comprising the agonist analog of exendin-4 according to claim 4 and a pharmaceutically acceptable carrier wherein the agonist analog of exendin-4 has a kidney clearance that is less than 50% of the kidney clearance of the agonist analog of exendin-4 without the C-terminal linked polyamino acid.

10. A method for treating diabetes, postprandial hyperglycemia, or impaired glucose tolerance comprising administering to a human in need of treatment for diabetes, postprandial hyperglycemia, or impaired glucose tolerance a therapeutically effective amount of a composition according to claim 6.

11. The method for treating diabetes according to claim 10.

12. The method of claim 11, wherein the diabetes is type II diabetes.