PEPTIDE AGONISTS OF GLP-1 ACTIVITY

• US 20110245165A1
• Filed: 04/29/2010
• Published: 10/06/2011
• Est. Priority Date: 07/12/1999
• Status: Abandoned Application

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Mikkelsen, Jens Damsgaard, Neve, Søren, LARSEN, Bjarne Due
• Application Number:
  US12/770,667
• Publication Number:
  US 20110245165A1
• Time in Patent Office: Days
• US Class Current: 514/6.7
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/57563 Vasoactive intestinal peptide [VIP]; Related peptides
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

Novel peptide agonists of GLP-1 activity useful for lowering blood glucose levels. The novel peptides comprise variants of the GLP-1 or the exendin-4 polypeptide sequence and are pharmacologically active and stable. These peptides are useful in the treatment of diseases that benefit from regulation of excess levels of blood glucose and/or regulation of gastric emptying, such as diabetes and eating disorders.

Claims

1. (canceled)

2. A method for treating type 2 diabetes mellitus in a subject in need thereof, said method comprising administering to said subject (i) a peptide conjugate comprising an exendin-4 variant coupled via its C-terminus to an amino acid sequence Z, wherein said exendin-4 variant comprises a sequence characterized by deletion of between 1 and 5 amino acid residues at positions corresponding to positions 34-38 of exendin-4(1-39) and wherein Z comprises from 4 to 20 Lys amino acid residues, or a pharmaceutically acceptable salt thereof;

and (ii) an antidiabetic agent each in an amount that together is effective for the treatment of type 2 diabetes mellitus.

3. The method of claim 2, wherein said antidiabetic agent is insulin or an oral hypoglycaemic agent.

4. The method of claim 3, wherein said antidiabetic agent is an oral hypoglycaemic agent selected from metformin, a sulfonyl urea, or a thiazolidinedione.

5. The method of claim 2, wherein said peptide conjugate is administered parenterally.

6. The method of claim 5, wherein said peptide conjugate is administered subcutaneously.

7. The method of claim 5, wherein said peptide conjugate is parenterally administered in a liquid dosage form.

8. The method of claim 2, wherein said peptide conjugate is formulated as a lyophilized solid and reconstituted prior to administration to said subject.

9. The method of claim 2, wherein said exendin-4 variant comprises a sequence characterized by deletion of between 1 and 3 amino acid residues at positions corresponding to positions 34-38 of exendin 4(1-39).

10. The method of claim 9, wherein said exendin-4 variant comprises a sequence characterized by deletion of 1, 2, or 3 Pro residues at positions corresponding to positions 36-38 of exendin-4(1-3 9).

11. The method of claim 2, wherein said amino acid sequence Z is Lys₄, Lys₅, Lys₆, Lys₇, Lys₈, Lys₉, or Lys₁₀.

12. The method of claim 2, wherein said peptide conjugate is administered as a free acid.

13. The method of claim 2, wherein said peptide conjugate is administered as a pharmaceutically acceptable salt.

14. The method of claim 2, wherein said exendin-4 variant is selected from desPro³⁶ exendin-4 (1-39), desPro³⁶Pro³⁷-exendin-4(1-39), and desPro³⁶Pro³⁷Pro³⁸-exendin-4(1-39).

15. The method of claim 14, wherein said peptide conjugate is selected from desPro³⁶-exendin-4(1 -3 9)-Lys₆-NH₂, desPro³⁶Pro³⁷-exendin-4(1-39)-Lys₆-NH₂, desPro³⁶Pro³⁷Pro³⁸-exendin-4(1-39)-Lys₆-NH₂, and pharmaceutically acceptable salts thereof.

16. The method of claim 15, wherein said peptide conjugate is selected from desPro³⁶-exendin-4(1-39)-Lys₆-NH₂, and pharmaceutically acceptable salts thereof.

17. The method of claim 16, wherein said antidiabetic agent is selected from insulin, metformin, a sulfonyl urea, and a thiazolidinedione.

18. The method of claim 16, wherein said antidiabetic agent is insulin.