Long lasting glucagon-like peptide 2 (GLP-2) for the treatment of gastrointestinal diseases and disorders

• US 7,737,251 B2
• Filed: 12/23/2005
• Issued: 06/15/2010
• Est. Priority Date: 02/16/2001
• Status: Expired due to Fees

• Current Assignee: ConjuChem LLC (Colabor Group, Inc.)
• Original Assignee: ConjuChem Biotechnologies, Inc. /Old/ (Colabor Group, Inc.)
• Inventors: Robitaille, Martin, Thibaudeau, Karen, Leger, Roger, Carette, Julie, Boudjellab, Nissab, Bridon, Dominique P.
• Primary Examiner(s): Tsang; Cecilia
• Assistant Examiner(s): AUDET, MAURY A
• Application Number:
  US11/318,323
• Publication Number:
  US 20060217304A1
• Time in Patent Office: 1,635 Days
• Field of Search: 514/12
• US Class Current: 530/308
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/38 Albumins
• CPC Class Codes: A61K 47/643 Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

This invention relates to glucagon-like peptide 2 (GLP-2) derivatives. In particular, this invention relates to GLP-2 peptide derivatives having an extended in vivo half-life, for the treatment or prevention of gastrointestinal disorders or diseases such as inflammatory bowel disease and other gastrointestinal functions, from any segment of the gastrointestinal tract, from the oesophagus to the anus.

Claims

1. A gastrointestinal tissue growth promoter derivative comprising:

a GLP-2 peptide having gastrointestinal tissue growth promoting activity; and

a single maleimide or a maleimido-containing group, wherein the maleimide or maleimido-containing group is coupled, optionally via a linker, to the GLP-2 peptide at a His or Lys residue,

wherein the GLP-2 peptide is of the sequence;

R₁-(Y₁)_m-X₁-X₂-X₃-X₄-X₅-Phe₆-Ser₇-Asp₈-(P₁)-X₁₄-Asp₁₅-X₁₆-X₁₇-Ala₁₈-X₁₉-X₂₀-X₂₁-Phe₂₂-(P₂)-Trp₂₅-Leu₂₆-X₂₇-X₂₈-Thr₂₉-Lys₃₀-P₃-(Y₂)_n-R₂(SEQ ID NOs;

2 and 29-252) wherein

X₁ is His or Tyr;

X₂ is Gly, D-Ala, Pro, Ile, Nor-Val, α

-aminobutyric acid, or an Ala-replacement amino acid conferring on said analog resistance to DPP-IV enzyme;

X₃ is Asp, Glu, Pro, HPro;

or X₂-X₃ are X_2ψ

(CH(OH)CH₂)X₃;

X_2ψ

(CH₂NH₂)X₃ or X_2ψ

(CHCH)X₃ wherein X₂ and X₃ are as defined above;

X₄is Gly or Ala;

X₅ is Ser or Ala;

P₁ is Glu-X₁₀-Asn-Thr-Ile (SEQ ID NO;

     253), Gly-X₁₀-Asn-Thr-Val (SEQ ID NO;

     254) or Tyr-Ser-Lys-Tyr (SEQ ID NO;

     255);

X₁₀is Met, Leu, Ile or an oxidatively stable Met-replacement amino acid;

X₁₄ is Leu or Lys;

X₁₆ is Asn, Lys or Ala;

X₁₇ is Leu or Lys;

X₁₉ is Ala or Thr;

X₂₀ is Arg, Lys, His or Ala;

X₂₁ is Asp or Lys;

X₂₇ is Ile or Leu;

X₂₈ is Gin or His;

P₂ is IIe-Asn, lIe-Ala or Val-Gin;

P₃ is a covalent bond, or is lIe, Ile-Thr, Ile-Thr-Asp or Ile-Thr-Asn;

R₁ is NH₂ or a N-terminal blocking group;

R₂ is COOH, CONH2 or a C-terminal blocking group;

Y₁ is one or two of Arg, Lys, and His;

Y₂ is one or two of Arg, Lys, and His; and

m and n are independently 0 or 1.

2. The gastrointestinal tissue growth promoter derivative of claim 1, wherein

X₁ is His or Tyr;

X₂ is Gly, D-Ala, Pro, or an Ala-replacement amino acid conferring on said analog resistance to DPP-JV enzyme;

X₃ is Asp, Glu, Pro, or HPro;

X₄ is Gly or Ala;

X₅ is Ser or Ala;

P₁ is Glu-X₁₀-Asn-Thr-Ile (SEQ ID NO;

     253), Gly-X₁₀-Asn-Thr-Val (SEQ ID NO;

     254) or Tyr-Ser-Lys-Tyr (SEQ ID NO;

     255);

X₁₀ is Met or an oxidatively stable Met-replacement amino acid;

X₁₄ is Leu;

X₁₆ is Asn, Lys or Ala;

X₁₇ is Leu;

X₁₉ isAla or Thr;

X₂₀ is Arg, Lys, His or Ala;

X₂₁ is Asp;

X₂₇ is lie or Leu;

X₂₈ is Gin or His;

P₂ is Ile-Asn, lIe-Ala or Val-Gln;

P₃ is a covalent bond, or is lIe, IIe-Thr, Ile-Thr-Asp or Ile-Thr-Asn;

R₁ is NH₂;

R₂ is a COOH, CONH₂ or a C-terminal blocking group;

Y₁ is one or two of Arg, Lys, and His;

Y₂ is one or two of Arg, Lys, and His; and

m and n are independently 0 or 1.

3. The gastrointestinal growth promoter derivative of claim 1, wherein γ

-maleimide-butyrylamide (GMBA), maleimidopropionic acid (MPA), (2-amino)ethoxy acetic acid (AEA)-MPA, ethylenediamine (EDA)-MPA, or 2-[2(2-amino)ethoxy]ethoxy acetic acid (AEEA)-MPA is coupled to the peptide.

4. The gastrointestinal tissue growth promoter derivative of claim 1, wherein (AEEA-EDA)-MPA, (AEEA-AEEA)-MPA, or (AEA-AEEA)-MPA is coupled to the peptide.

5. The gastrointestinal growth promoter derivative of claim 1, wherein the GLP-2 peptide is of the sequence:

R₁ -His₁ -Gly₂-Asp₃-Gly₄-Ser₅-Phe₆-Ser₇-Asp₈-Glu₉-Met₁₀-Asn₁₁-Thr₁₂-Ilel₁₃-X₁₄-Aspi₁₅-X₁₆-X₁₇-Ala₁₈-Ala₁₉-Arg₂₀-X₂₁-Phe₂₂-Ile₂₃-Asn₂₄-Trp₂₅Leu₂₆-Ile₂₇-Gln₂₈Thr₂₉Lys₃₀-Ile₃₁-Thr₃₂-Asp₃₃-(Y₂)_n-CONH₂ (SEQ ID NOs;

256-258);

wherein X₁₄ is Leu or Lys;

X₁₆ is Asn or Lys;

X₁₇ is Leu or Lys;

X₂₁ is Asp or Lys;

R₁ is NH₂ or a N-terminal blocking group;

Y₂ is one or two of Arg, Lys, and His; and

n is 0 or 1.

6. The gastrointestinal tissue growth promoter derivative of claim 5, wherein n is 1 and Y₂ is Lys.

7. The gastrointestinal growth promoter derivative of claim 5, wherein the gastrointestinal growth promoter derivative is

MPA-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala -Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH₂ (SEQ ID NO:

8);

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Lys (MPA)-Leu-Ala -Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH₂ (SEQ ID NO;

     9);

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Lle-Leu-Asp-Asn-Leu-Ala-Ala -Arg-Asp-Phe-Ile-Asn-Trp-Leu-lle-GLn-Thr-Lys-Ile-Thr-Asp-Lys(MPA)-CONH₂ (SEQ ID NO;

     10);

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-lle-Leu-Asp-Lys (AEEA-MPA) -Leu-Ala- Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH₂ (SEQ ID NO;

     11);

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala -Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys(AEEA-MPA)-CONH₂ (SEQ ID NO;

     12);

or

MPA-AEEA-His-Gly-Asp-Gly -Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn -Leu-Ala- Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH₂ (SEQ ID NO;

     13).

8. The gastrointestinal growth promoter derivative of claim 5, wherein the gastrointestinal growth promoter derivative is

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Lys (MPA)-Leu-Ala -Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH₂ (SEQ ID NO:

9).

9. The gastrointestinal growth promoter derivative of claim 3, wherein the gastrointestinal growth promoter derivative is

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala -Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys(MPA)-CONH₂ (SEQ ID NO:

10).

10. The gastrointestinal growth promoter derivative of claim 5, wherein the gastrointestinal growth promoter derivative is

MPA-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala -Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH₂ (SEQ ID NO:

8).

23. A pharmaceutical composition comprising the gastrointestinal tissue growth promoter derivative of claim 1 or 2;

and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising the gastrointestinal tissue growth promoter derivative of claim 5;

and a pharmaceutically acceptable carrier.

25. A method for the treatment of a gastrointestinal disorder or disease in a subject comprising administering to a subject in need thereof an effective amount of the gastrointestinal growth promoter derivative of claim 1, wherein said gastrointestinal disorder or disease is inflammatory bowel disease, an ulcer or inflammatory disease of the small intestinal tract mucosa, small intestinal damage due to a toxic or a chemotherapeutic agent, or a disease or disorder caused by loss of small intestine mucosal function.

26. The method of claim 25, wherein the gastrointestinal disorder or disease is inflammatory bowel disease.

27. The method of claim 25 wherein said gastrointestinal disorder or disease is a disorder or disease caused by loss of small intestine mucosal function.

28. The method of claim 26, wherein the inflammatory bowel disease is ulcerative colitis.

29. The method of claim 26, wherein the inflammatory bowel disease is Crohn'"'"'s disease.

30. The method of claim 27 wherein the subject is undergoing extended parenteral feeding.

31. The method of claim 27 wherein the subject has undergone resection of the small intestine.

32. The method of claim 31 wherein the subject has short bowel syndrome.

33. The method of claim 27 wherein the gastrointestinal disorder or disease is a malabsorption syndrome.

34. A method for the promotion of gastrointestinal tissue growth in a subject comprising administering to a subject in need thereof an effective amount of the gastrointestinal growth promoter derivative of claim 1.

35. A method for the treatment of a gastrointestinal disorder or disease treatable by increasing small intestinal mass and consequent small intestine mucosal function in a subject comprising administering to a subject in need thereof an effective amount of the gastrointestinal growth promoter derivative of claim 1.

36. A method for the determination of the intestinotrophic activity of a hormone comprising:

(a) coadministering the hormone with an intestinotrophic amount of a gastrointestinal growth promoter derivative of claim 1 to a test subject;

(b) assessing the subsequent growth of small and large intestine tissue in the test subject; and

(c) determining whether the growth of the small and/or Large intestine in the test subject is enhanced relative to control subjects treated with said gastrointestinal growth promoter derivative.

11. A conjugate formed by covalently coupling a gastrointestinal tissue growth promoter derivative to a blood protein,

wherein the gastrointestinal tissue growth promoter derivative comprises:

a GLP-2 peptide having gastrointestinal tissue growth promoting activity;

a single maleimide or a maleimido-containing group, wherein the maleimide or maleimido-containing group is coupled, optionally via a linker, to the GLP-2 peptide at a His or Lys residue, and

wherein the GLP-2 peptide is of the sequence;

R₁ (Y₁)_m-X₁ -X₂-X₃-X₄-X₅-Phe₆-Ser₇-Asp₈-(P₁)-X₁₄-Asp₁₅-X₁₆-X₁₇-Ala₁₈-X₁₉-X₂₀-X₂₁ -Phe₂₂-(P₂)-Trp₂₅-Leu₂₆-X₂₇-X₂₈-Thr₂₉-Lys₃₀-P₃-(Y₂)_n-R₂ (SEQ ID NOs;

2 and 29-252) wherein

X₁ is His or Tyr;

X₂ is Gly, D-Ala, Pro, lle, Nor-Val, α

-aminobutyric acid, or an Ala-replacement amino acid conferring on said analog resistance to DPP-IV enzyme;

X₃ is Asp, Glu, Pro, HPro;

or X₂-X₃are X_2ψ

(CH(OH)CH₂)X₃;

X₂ ψ

(CH₂NH₂)X₃ or X₂ψ

(CHCH)X₃ wherein X₂ and X₃ are as defined above;

X₄ is Gly or Ala;

X₅ is Ser or Ala;

P₁ is Glu-X₁₀-Asn-Thr-Ile (SEQ ID NO;

     253) Gly-X₁₀-Asn-Thr-Val (SEQ ID NO;

     254) or Tyr-Ser-Lys-Tyr (SEQ ID NO;

     255);

X₁₀ is Met, Leu, Ile or an oxidatively stable Met-replacement amino acid;

X₁₄ is Leu or Lys;

X₁₆ is Asn, Lys or Ala;

X₁₇ is Leu or Lys;

X₁₉ is Ala or Thr;

X₂₀ is Arg, Lys, His or Ala;

X₂₁ is Asp or Lys;

X₂₇ is Ile or Leu;

X₂₈ is Gln or His;

P₂ is Ile-Asn, Ile-Ala or Val-Gln;

P₃ is a covalent bond, or is lle, Ile-Thr, Ile-Thr-Asp or Ile-Thr-Asn;

R₁ is NH₂ or a N-terminal blocking group;

R₂ is COOH, CONH₂ or a C-terminal blocking group;

Y₁ is one or two of Arg, Lys, and His;

Y₂ is one or two of Arg, Lys, and His; and

m and n are independently 0 or 1.

12. The conjugate of claim 11, wherein

X₁ is His or Tyr;

X₂ is Gly, D-Ala, Pro, or an Ala-replacement amino acid conferring on said analog resistance to DPP-IV enzyme;

X₃ is Asp, Glu, Pro, or HPro;

X₄ is Gly or Ala;

X₅ is Ser or Ala;

P₁ is Glu-X₁₀-Asn-Thr-Ile (SEQ ID NO;

     253), Gly-X₁₀-Asn-Thr-Val (SEQ ID NO;

     254) or Tyr-Ser-Lys-Tyr (SEQ ID NO;

     255);

X₁₀ is Met or an oxidatively stable Met-replacement amino acid;

X₁₄ is Leu;

X₁₆ is Asn, Lys or Ala;

X₁₇ is Leu;

X₁₉ is Ala or Thr;

X₂₀ is Arg, Lys, His or Ala;

X₂₁ is Asp;

X₂₇ is Ile or Leu;

X₂₈ is Gln or His;

P₂ is Ile-Asn, Ile-Ala or Val-Gln;

P₃ is a covalent bond, or is Ile, Ile-Thr, Ile-Thr-Asp or Ile-Thr-Asn;

R₁is NH_2;

R₂ is a COOH, CONH₂ or a C-terminal blocking group;

Y₁ is one or two of Arg, Lys, and His;

Y₂ is one or two of Arg, Lys, and His; and

m and n are independently 0 or 1.

13. The conjugate of claim 11, wherein the coupling of the gastrointestinal tissue growth promoter derivative is to a thiol group on the blood protein.

14. The conjugate of claim 11, 12, or 13 wherein the blood protein is albumin.

15. The conjugate of claim 11, wherein the GLP-2 peptide is of the sequence:

R₁-His₁-Gly₂-Asp₃-Gly₄-Ser₅-Phe₆-Ser₇-Asp₈-Glu₉-Met₁₀-Asn₁₁-Ile₁₃-X₁₄-Asp₁₅-X₁₆-X₁₇-Ala₁₈-Ala₁₉-Arg₂₀-X₂₁ -Phe₂₂-Ile₂₃-Asn₂₄-Trp₂₅-Leu₂₆-Ile₂₇-Gln₂₈-Thr₂₉-Lys₃₀-Ile₃₁-Thr₃₂-Asp₃₃-(Y₂)_n-CONH₂ (SEQ ID NOs;

256-258);

wherein X₁₄ is Leu or Lys;

X₁₆ is Asn or Lys;

X₁₇ is Leu or Lys;

X₂₁ is Asp or Lys;

R₁ is NH₂ or a N-terminal blocking group;

Y₂ is one or two of Arg, Lys, and His; and

n is 0 or 1.

16. The conjugate of claim 15, wherein n is 1 and Y₂ is Lys.

17. The conjugate of claim 15, wherein the blood protein is albumin.

18. The conjugate of claim 15, wherein the GLP-2 peptide is of the sequence:

MPA-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala -Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH₂ (SEQ ID NO;

     8);

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Lys (MPA)-Leu-Ala -Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH2 (SEQ ID NO;

     9);

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala -Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys(MPA)-CONH₂ (SEQ ID NO;

     10);

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Lys (AEEA-MPA) -Leu-Ala- Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-lle-Gln-Thr-Lys-Ile-Thr-Asp-CONH₂ (SEQ ID NO;

     11);

His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala -Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys(AEEA-MPA)-CONH₂ (SEQ ID NO;

     12);

or

MPA-AEEA-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn -Leu-Ala- Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH₂ (SEQ ID NO;

     13).

19. A composition comprising the conjugate of claim 11, 12, or 13;

and a pharmaceutically acceptable carrier.

20. A composition comprising the conjugate of claim claim 11, 12, 13 wherein the blood protein is albumin and a pharmaceutically acceptable carrier.

21. A composition comprising the conjugate of claim 15;

and a pharmaceutically acceptable carrier.

22. A composition comprising the conjugate of claim 17;

and a pharmaceutically acceptable carrier.

37. A method for the promotion of gastrointestinal tissue growth in a subject comprising administering to a subject in need thereof an effective amount of the conjugate of claim 11.

38. A method for the treatment of a gastrointestinal disorder or disease treatable by increasing small intestinal mass and consequent small intestine mucosal function in a subject comprising administering to a subject in need thereof an effective amount of the conjugate of claim 11.

39. A method for the treatment of a gastrointestinal disorder or disease in a subject comprising administering to a subject in need thereof an effective amount of the conjugate of claim 11, wherein said gastrointestinal disorder or disease is inflammatory bowel disease, an ulcer or inflammatory disease of the small intestinal tract mucosa, small intestinal damage due to a toxic or a chemotherapeutic agent, or a disease or disorder caused by loss of small intestine mucosal function.

40. The method of claim 39, wherein the gastrointestinal disorder or disease is inflammatory bowel disease.

41. The method of claim 39 wherein said gastrointestinal disorder or disease is a disorder or disease caused by loss of small intestine mucosal function.

42. The method of claim 40, wherein the inflammatory bowel disease is ulcerative colitis.

43. The method of claim 40, wherein the inflammatory bowel disease is Crohn'"'"'s disease.

44. The method of claim 41 wherein the subject is undergoing extended parenteral feeding.

45. The method of claim 41 wherein the subject has undergone resection of the small intestine.

46. The method of claim 45 wherein the subject has short bowel syndrome.

47. The method of claim 41 wherein the gastrointestinal disorder or disease is a malabsorption syndrome.

48. The method of any one of claims 39-37 and 41-38 wherein the blood protein is albumin.

49. A method for the treatment of a gastrointestinal disorder or disease in a subject comprising administering to a subject in need thereof an effective amount of the conjugate of claim 18, wherein said gastrointestinal disorder or disease is inflammatory bowel disease, an ulcer or inflammatory disease of the small intestinal tract mucosa, small intestinal damage due to a toxic or a chemotherapeutic agent, or a disease or disorder caused by loss of small intestine mucosal function.

50. A method for the promotion of gastrointestinal tissue growth in a subject comprising administering to a subject in need thereof an effective amount of the conjugate of claim 18.

51. A method for the treatment of a gastrointestinal disorder or disease treatable by increasing small intestinal mass and consequent small intestine mucosal function in a subject comprising administering to a subject in need thereof an effective amount of the conjugate of claim 18.

52. A method for extending the in vivo half-life of a GLP-2 peptide comprising covalently bonding in vivo or ex vivo the GLP-2 peptide to a blood protein,

wherein the GLP-2 peptide is of the sequence:

R₁-(Y₁)_m -X₁-X₂-X₃-X₄-X₅-Phe₆-Ser₇-Asp₁₈-(P₁)-X₁₄-Asp₁₅-X₁₆-X₁₇-Ala₁₈-X₁₉-X₂₀-X₂₁ -Phe₂₂-(P₂)-Trp₂₅-Leu₂₆-X₂₇-X₂₈-Thr₂₉-Lys₃₀-P₃-(Y₂)_n-R₂ (SEQ ID NOs;

2 and 29-252) wherein

X₁ is His or Tyr;

X₂ is Gly, D-Ala, Pro, Ile, Nor-Val, α

-aminobutyric acid, or an Ala-replacement amino acid conferring on said analog resistance to DPP-IV enzyme;

X₃ is Asp, Glu, Pro, HPro;

or X₂-X₃ are X_2ψ

(CH(OH)CH₂)X₃;

X_2ψ

(CH₂NH₂)X₃ or X_2ψ

(CHCH)X₃ wherein X₂ and X₃ are as defined above;

X₄ is Gly or Ala;

X₅ is Ser or Ala;

P₁ is Glu-X10-Asn-Thr-Ile (SEQ ID NO;

     253), Gly-X₁₀-Asn-Thr-Val (SEQ ID NO;

     254) or Tyr-Ser-Lys-Tyr (SEQ ID NO;

     255);

X₁₀ is Met, Leu, Ile or an oxidatively stable Met-replacement amino acid;

X₁₄ is Leu or Lys;

X₁₆ is Asn, Lys or Ala;

X₁₇ is Leu or Lys;

X₁₉ is Ala or Thr;

X₂₀ is Arg, Lys, His or Ala;

X₂₁ is Asp or Lys;

X₂₇ is Ile or Leu;

X₂₈ is Gln or His;

P₂ is Ile-Asn, Ile-Ala or Val-Gln;

P₃ is a covalent bond, or is Ile, Ile-Thr, Ile-Thr-Asp or Ile-Thr-Asn;

R₁ is NH₂ or a N-terminal blocking group;

R₂ is COOH, CONH₂ or a C-terminal blocking group;

Y₁ is one or two of Arg, Lys, and His;

Y₂ is one or two of Arg, Lys, and His; and

m and n are independently 0 or 1.