Long-acting exendins and exendin agonists

• US 20040092443A1
• Filed: 04/08/2003
• Published: 05/13/2004
• Est. Priority Date: 08/07/1996
• Status: Abandoned Application

• Current Assignee: Yeda Research and Development Co. Ltd. (Weizmann Institute of Science)
• Original Assignee: Yeda Research and Development Co. Ltd. (Weizmann Institute of Science)
• Inventors: Tsubery, Haim, Fridkin, Matityahu, Shechter, Yoram
• Application Number:
  US10/408,262
• Publication Number:
  US 20040092443A1
• Time in Patent Office: Days
• US Class Current: 514/7.3
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/555 pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells

Abstract

Long-acting exendin or exendin agonist derivatives of the formula (X)_n-Z are provided, wherein X is a radical 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenyl-methoxycarbonyl (FMS), Z is the residue of an exendin or exendin agonist linked to the radical X through an amino or hydroxyl group, and n is 1 to 3. The exendin is exendin-3 or exendin-4. The derivatives are useful for prevention or treatment of conditions, diseases or disorders that can be treated by an exendin, for example for prevention of hyperglycemia and for treatment of diabetes mellitus, e.g. non-insulin dependent diabetes mellitus, insulin-dependent diabetes mellitus, and gestational diabetes mellitus.

Claims

1. An exendin or exendin agonist derivative of the formula:

(X)_n-Z

wherein X is a radical 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS), Z is the residue of an exendin or exendin agonist linked to the radical X through an amino or hydroxyl group, and n is 1 to 3.

2. An exendin derivative of claim 1 wherein said exendin is exendin-4 [SEQ. ID. NO:

1].

3. The exendin-4 derivative of claim 2 selected from the group consisting of the derivatives herein designated Fmoc-exendin-4, (Fmoc)₂-exendin-4, (Fmoc)₃-exendin-4, FMS-exendin-4, (FMS)₂-exendin-4 and (FMS)₃-exendin-4.

5. An exendin derivative of claim 1 wherein said exendin is exendin-3 [SEQ. ID. NO:

2].

6. The exendin-3 derivative of claim 5 selected from the group consisting of the derivatives herein designated Fmoc-exendin-3, (Fmoc)₂-exendin-3, (Fmoc)₃-exendin-3, FMS-exendin-3, (FMS)₂-exendin-3 and (FMS)₃-exendin-3.

7. An exendin agonist derivative of claim 1 wherein said exendin agonist is an exendin-3 or exendin-4 agonist.

8. An exendin agonist derivative of claim 7 wherein said exendin agonist is an exendin-4 agonist selected from the group of the sequences consisting of SEQ ID NO:

3, SEQ ID NO;

4, SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

7, SEQ ID NO;

8, SEQ ID NO;

9, and SEQ ID NO;

10.

9. A pharmaceutical composition comprising an exendin or exendin agonist derivative of claim 1, and a pharmaceutically acceptable carrier

11. The pharmaceutical composition according to claim 9 for prevention of hyperglycemia.

13. The pharmaceutical composition according to claim 9 for treatment of diabetes mellitus.

14. The pharmaceutical composition according to claim 13 for treatment of non-insulin dependent diabetes mellitus, insulin-dependent diabetes mellitus, or gestational diabetes mellitus.

17. A method for prevention of hyperglycemia which comprises administering to an individual in need an effective insulinotropic amount of an exendin or exendin agonist derivative of claim 1.

18. A method for treatment of diabetes mellitus which comprises administering to an individual in need an effective amount of an exendin or exendin agonist derivative of claim 1.

19. The method of claim 18 wherein said diabetes mellitus is selected from the group consisting of non-insulin dependent diabetes mellitus, insulin-dependent diabetes mellitus, and gestational diabetes mellitus.

4. The exendin-4 derivative herein designated (FMS)₃-exendin-4.

10. A pharmaceutical composition comprising (FMS)₃-exendin-4 and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 10 for prevention of hyperglycemia.

15. The pharmaceutical composition according to claim 10 for treatment of diabetes mellitus.

16. The pharmaceutical composition according to claim 15 for treatment of non-insulin dependent diabetes mellitus, insulin-dependent diabetes mellitus, or gestational diabetes mellitus.