Novel exendin agonist compounds

• US 20070010656A1
• Filed: 08/28/2006
• Published: 01/11/2007
• Est. Priority Date: 08/08/1997
• Status: Active Grant

• Current Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Prickett, Kathryn, Beeley, Nigel
• Granted Patent: US 7,858,740 B2
• Time in Patent Office: Days
• US Class Current: 530/326
• 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: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/57563 Vasoactive intestinal peptide [VIP]; Related peptides

Abstract

Novel exendin agonist compounds are provided. These compounds are useful in treating Type I and II diabetes and conditions which would be benefited by lower plasma glucose and delaying and/or slowing gastric emptying

Claims

1. An exendin agonist peptide compound of the formula (I) [SEQ. ID. NO. 4]:

Xaa₁Xaa₂ Xaa₃ Gly Thr Xaa₄ Xaa₅ Xaa₆ Xaa₇ Xaa₈ Ser Lys Gln Xaa₉ Glu Glu Glu Ala Val Arg Leu Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Leu Lys Asn Gly Gly Xaa₁₄ Ser Ser Gly Ala Xaa₁₅ Xaa₁₆ Xaa₁₇ Xaa₁₈-Z

wherein

Xaa₁ is His, Arg or Tyr;

Xaa₂ is Ser, Gly, Ala or Thr;

Xaa₃ is Asp or Glu;

Xaa₄ is Phe, Tyr or naphthylalanine;

Xaa₅ is Thr or Ser;

Xaa₆ is Ser or Thr;

Xaa₇ is Asp or Glu;

Xaa₈ is Leu, Ile, Val, pentylglycine or Met;

Xaa₉ is Leu, Ile, pentylglycine, Val or Met;

Xaa₁₀ is Phe, Tyr or naphthylalanine;

Xaa₁₁ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met;

Xaa₁₂ is Glu or Asp;

Xaa₁₃ is Trp, Phe, Tyr, or naphthylalanine;

Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine;

Xaa₁₈ is Ser, Thr or Tyr; and

Z is —

OH or —

NH₂;

with the proviso that the compound does not have the formula of either SEQ. ID. NOS. 1 or 2; and

pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 wherein Xaa₁ is His or Tyr.

3. The compound according to claim 2 wherein Xaa₁ is His.

4. The compound according to claim 2 wherein Xaa₂ is Gly.

5. The compound according to claim 4 wherein Xaa₉ is Leu, pentylglycine or Met.

6. The compound according to claim 5 wherein Xaa₁₃ is Trp or Phe.

7. The compound according to claim 6 wherein Xaa₄ is Phe or naphthylalanine;

Xaa₁₀ is Phe or naphthylalanine;

Xaa₁₁ is Ile or Val and Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independently selected from Pro, homoproline, thioproline or N-alkylalanine.

8. The compound according to claim 7 wherein Xaa₁₈ is Ser or Tyr.

9. The compound according to claim 8 wherein Xaa₁₈ is Ser.

10. The compound according to claim 9 wherein Z is —

NH₂.

11. The compound according to claim 1 wherein Xaa₂ is Gly.

12. The compound according to claim 1 wherein Xaa₉ is Leu, pentylglycine or Met.

13. The A compound according to claim 1 wherein Xaa₁₃ is Trp or Phe.

14. The compound according to claim 1 wherein Xaa₄ is Phe or naphthylalanine;

Xaa₁₀ is Phe or naphthylalanine;

Xaa₁₁ is Ile or Val and Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independently selected from Pro, homoproline, thioproline or N-alkylalanine.

15. The compound according to claim 1 wherein Xaa₁₈ is Ser or Tyr.

16. The compound according to claim 1 wherein Z is —

NH₂.

17. The compound according to claim 1 which has an amino acid sequence selected from SEQ. ID. NOS.5to 35.

22. A composition comprising a compound of claim 1 in a pharmaceutically acceptable carrier.

38. The compound according to claim 22 which has an amino acid sequence selected from SEQ. ID. NOS. 36-39.

40. A composition comprising a compound of claim 38 in a pharmaceutically acceptable carrier.

18. An exendin agonist peptide compound of the formula (I) [SEQ. ID. NO. 4]:

Xaa₁ Xaa₂ Xaa₃ Gly Thr Xaa₄ Xaa₅ Xaa₆ Xaa₇ Xaa₈ Ser Lys Gln Xaa₉ Glu Glu Glu Ala Val Arg Leu Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Leu Lys Asn Gly Gly Xaa₁₄ Ser Ser Gly Ala Xaa₁₅ Xaa₁₆ Xaa₁₇ Xaa₁₈-Z

wherein

Xaa₁ is His or Arg;

Xaa₂ is Gly or Ala;

Xaa₃ is Asp or Glu;

Xaa₄ is Phe or naphthylalanine;

Xaa₅ is Thr or Ser;

Xaa₆ is Ser or Thr;

Xaa₇ is Asp or Glu;

Xaa₈ is Leu or pentylglycine;

Xaa₉ is Leu or pentylglycine;

Xaa₁₀ is Phe or naphthylalanine;

Xaa₁₁ is Ile, Val or tert-butylglycine;

Xaa₁₂ is Glu or Asp;

Xaa₁₃ is Trp or Phe;

Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independently Pro, homoproline, thioproline or N-methylalanine;

Xaa₁₈ is Ser or Tyr; and

Z is —

OH or —

NH₂;

with the proviso that the compound does not have the formula of either SEQ. ID. NOS. 1 or 2; and

pharmaceutically acceptable salts thereof.

19. The compound according to claim 18 which has an amino acid sequence selected from SEQ. ID. NOS. 5, 6, 17, 18, 19, 22, 24, 31, 32 and 35.

20. The compound according to claim 18 which is exendin-3 acid.

21. The compound according to claim 18 which is exendin-4 acid.

23. A composition comprising a compound of claim 19 in a pharmaceutically acceptable carrier.

24. An exendin agonist peptide compound of the formula (II) [SEQ. ID. NO. 40]:

Xaa₁ Xaa₂ Xaa₃ Gly Thr Xaa₄ Xaa₅ Xaa₆ Xaa₇ Xaa₈ Ser Lys Gln Xaa₉ Glu Glu Glu Ala Val Arg Leu Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Leu XI Gly Gly Xaa₁₄ Ser Ser Gly Ala Xaa₁₅ Xaa₁₆ Xaa₁₇ Xaa₁₈-Z

wherein

Xaa₁ is His, Arg, Tyr or 4-imidazopropionyl;

Xaa₂ is Ser, Gly, Ala or Thr;

Xaa₃ is Asp or Glu;

Xaa₄ is Phe, Tyr or naphthylalanine;

Xaa₅ is Thr or Ser;

Xaa₆ is Ser or Thr;

Xaa₇ is Asp or Glu;

Xaa₈ is Leu, Ile, Val, pentylglycine or Met;

Xaa₉ is Leu, Ile, pentylglycine, Val or Met;

Xaa₁₀ is Phe, Tyr or naphthylalanine;

Xaa₁₁ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met;

Xaa₁₂ is Glu or Asp;

Xaa₁₃ is Trp, Phe, Tyr, or naphthylalanine;

X₁ is Lys Asn, Asn Lys, Lys-NHε

-R Asn, Asn Lys-NHε

-R where R is Lys, Arg, C₁-C₁₀ straight chain or branched alkanoyl or cycloalkylalkanoyl

Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine;

Xaa₁₈ is Ser, Thr or Tyr; and

Z is —

OH or —

NH₂;

with the proviso that the compound does not have the formula of either SEQ. ID. NOS. 1 or 2; and

pharmaceutically acceptable salts thereof.

25. The compound according to claim 24 wherein Xaa₁ is His, Tyr or 4-imidazopropionyl.

26. The compound according to claim 25 wherein Xaa₁ is His or 4-imidazopropionyl.

27. The compound according to claim 24 wherein Xaa₂ is Gly.

28. The compound according to claim 24 wherein Xaa₉ is Leu, pentylglycine or Met.

29. The compound according to claim 24 wherein Xaa₁₃ is Trp or Phe.

30. The compound according to claim 24 wherein X₁ is Lys Asn, or Lys-NHε

-R Asn, where R is Lys, Arg, C1-C10 straight chain or branched alkanoyl.

31. The compound according to claim 24 wherein Xaa₄ is Phe or naphthylalanine;

Xaa₁₀ is Phe or naphthylalanine;

Xaa₁₁ is Ile or Val and Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independently selected from Pro, homoproline, thioproline or N-alkylalanine.

32. The compound according to claim 24 wherein Xaa₁₈ is Ser or Tyr.

33. The compound according to claim 32 wherein Xaa₁₈ is Ser.

34. The compound according to claim 24 wherein Z is —

NH₂.

35. The compound according to claim 24 wherein Xaa₄ is Phe or naphthylalanine;

Xaa₁₀ is Phe or naphthylalanine;

Xaa₁₁ is Ile or Val, X₁ is Lys Asn, or Lys-NHε

-R Asn, where R is Lys, Arg, C₁-C₁₀ straight chain or branched alkanoyl and Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independently selected from Pro, homoproline, thioproline or N-alkylalanine.

36. The compound according to claim 35 wherein Xaa₁₈ is Ser or Tyr.

37. The compound according to claim 35 wherein Z is —

NH₂.

39. A composition comprising a compound of claim 24 in a pharmaceutically acceptable carrier.