Selective glucagon-like-peptide-2 (GLP-2) analogues

• US 10,092,648 B2
• Filed: 02/04/2014
• Issued: 10/09/2018
• Est. Priority Date: 11/08/2006
• Status: Expired due to Fees

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Larsen, Bjarne Due, Petersen, Yvette Miata
• Primary Examiner(s): Chandra, Gyan
• Application Number:
  US14/172,680
• Publication Number:
  US 20140154214A1
• Time in Patent Office: 1,708 Days
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

GLP-2 analogs are disclosed which comprise one of more substitutions as compared to h[Gly2]GLP-2 and which may have the property of an increased small intestine/colon and stomach/colon selectivity. More particularly, preferred GLP-2 analogs disclosed herein comprise substitutions at one or more of positions 11, 16, 20, 24 and/or 28 of the wild-type GLP-2 sequence, optionally in combination with further substitutions at position 2 and one or more of positions 3, 5, 7, and 10, and/or a deletion of one or more of amino acids 31 to 33 and/or the addition of a N-terminal or C-terminal stabilizing peptide sequence. The analogs are particularly useful for the prophylaxis or treatment of stomach and bowel-related disorders and for ameliorating side effects of chemotherapy.

Claims

1. A glucagon-like peptide 2 (GLP-2) analogue represented by general Formula II:

R¹—

Z¹-His-X2-X3-Gly-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-Ala-X19-X20-X21-Phe-Ile-X24-Trp-Leu-Ile-X28-Thr-Lys-X31-X32-X33-Z²—

R² 

 

(SEQ ID NO;

     4)

wherein;

R¹ is hydrogen, C_1-4 alkyl, methyl, acetyl, formyl, benzoyl or trifluoroacetyl;

X2 is Gly;

X3 is Glu or Asp;

X5 is Ser or Thr;

X6 is Phe;

X7 is Ser or Thr;

X8 is Asp;

X9 is Glu;

X10 is Leu;

X11 is Asn, Ala, Glu, or Ser;

X12 is Thr;

X13 is lie;

X14 is Leu;

X15 is Asp or Glu;

X16 is Ala, Glu, or Ser;

X17 is Leu;

X19 is Ala;

X20 is Ala, Glu, or Ser;

X21 is Asp;

X24 is Ala or Ser;

X28 is Ala, Glu, or Ser;

X31 is lie;

X32 is Thr;

X33 is Asp;

R² is NH₂ or OH;

Z¹ and Z² are independently absent or a peptide sequence of 1-10 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Met and Orn;

or a pharmaceutically acceptable salt thereof.

2. A GLP glucagon-like peptide 2 (GLP-2) analogue according to claim 1 wherein:

X11 is Ala or Ser;

X16 is Ala or Ser;

X20 is Ala or Ser;

X24 is Ala or Ser;

or

X28 is Ala or Ser.

3. The GLP-2 analogue of claim 1, wherein the GLP-2 analogue has at least 60% amino acid sequence identity to wild-type GLP-2 (1-33) and has the biological activity of causing an increase in intestinal mass in vivo.

4. The GLP-2 analogue of claim 1, wherein the GLP-2 analogue comprises more than one of the substitutions at positions X11, X16, X20, X24 and/or X28 and/or one of more of said substitutions in combination with one or more substitutions at positions X3, X5, and/or X7.

5. The GLP-2 analogue of claim 1 which is disclosed in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

6. The GLP-2 analogue of claim 5 which is:

7. The GLP-2 analogue of claim 1 wherein each of X11, X16, X20, X24 and X28 is independently selected from Ala and Ser, and wherein the analogue has preferential growth promoting activity for the small intestine over the colon.

8. The GLP-2 analogue of claim 7 wherein X11 and X16 are both Ala, and X20, X24 and X28 are independently selected from Ala and Ser.

9. The GLP-2 analogue of claim 7 comprising one of the following combinations of residues at positions X11, X16, X20, X24 and X28:

Ser/Ser/Ser/Ser/Ser;

Ala/Ala/Ser/Ser/Ser;

Ala/Ala/Ala/Ala/Ser;

Ser/Ala/Ser/Ser/Ser;

Ala/Ala/Ala/Ser/Ala;

Ala/Ala/Ser/Ala/Ala;

Ser/Ala/Ala/Ala/Ala;

Ser/Ala/Arg/Ala/Ala;

Ala/Ser/Ala/Ser/Ala; and

Ala/Ala/Ala/Ala/Ala.

10. The GLP-2 analogue of claim 7 which is:

11. A pharmaceutical composition comprising a GLP-2 analogue of claim 1, or a salt thereof, in admixture with a carrier.

12. The pharmaceutical composition of claim 11, wherein the GLP-2 analogue is a pharmaceutically acceptable acid addition salt.

13. The pharmaceutical composition of claim 11, which is formulated as a liquid suitable for administration by injection or infusion, or which is formulated to cause slow release of said GLP-2 analogue.

14. A method of treating a stomach and bowel-related disorder in a patient in need thereof by administering an effective amount of a GLP-2 analogue of claim 1.

15. The method of claim 14, wherein the stomach and bowel-related disorder is malabsorption syndromes, inflammatory bowel disease, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, enteritis, regional enteritis, ulcerative colitis, small intestine damage or short bowel syndrome.

16. The method of claim 14, wherein the stomach and bowel-related disorder is radiation enteritis, infectious or post-infectious enteritis, or small intestinal damage due to toxic or other chemotherapeutic agents.

17. A therapeutic kit comprising a cancer chemotherapy drug and a GLP-2 analogue according to claim 1 in combination with a pharmaceutically acceptable carrier.