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

• US 8,642,727 B2
• Filed: 11/08/2007
• Issued: 02/04/2014
• 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:
  US12/514,042
• Publication Number:
  US 20120004392A1
• Time in Patent Office: 2,280 Days
• Field of Search: None
• US Class Current: 530/324
• 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 analogues 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 analogues 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 analogues 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 the general Formula I:

R¹-Z¹-His-X2-X3-Gly-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-Phe-Ile-X24-Trp-Leu-Ile-X28-Thr-Lys-X31-X32-X33-Z²-R² 

 

(SEQ ID NO;

2)

wherein;

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

X2 is Gly, Ala or Sar;

X3 is Glu or Asp;

X5 is Ser or Thr;

X6 is Phe or Pro or a conservative substitution;

X7 is Ser or Thr;

X8 is Asp or Ser or a conservative substitution;

X9 is Glu or Asp or a conservative substitution;

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

X11 is Y1;

X12 is Thr or Lys or a conservative substitution;

X13 is Ile, Glu or Gln or a conservative substitutio;

X14 is Leu, Met or Nle or a conservative substitution;

X15 is Asp or Glu;

X16 is Y2;

X17 is Leu or Glu or a conservative substitution;

X18 is Ala or Aib or a non-conservative substitution;

X19 is Ala or Thr or a conservative substitution;

X20 is Y3

X21 is Asp or Ile or a conservative substitution;

X24 is Y4;

X28 is Y5;

X31 is Pro, Ile or deleted;

X32 is Thr or deleted;

X33 is Asp, Asn or deleted;

R² is NH₂ or OH;

wherein

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; and

the hydrophaticity profile (HPP) of the residues X11, X16, X20, X24, X28 of formula I calculated as

HPP=Σ

hpi_X11+hpi_X16+hpi_X20+hpi_X24+hpi_X28 is ≧

−

10

wherein

Y₁, Y₂, Y₄, and Y₅ can individually be selected from the group consisting of Asn, Asp, Glu, Gln, Lys, His, Arg, Ala, Ser, Thr, Pro, Gly, Leu, Ile, Val, Met or Phe; and

Y₃ can be selected from the group consisting of Asn, Asp, Glu, Gln, His, Arg, Ala, Ser, Thr, Pro, Gly, Leu, Ile, Val, Met or Phe;

with the proviso that when X20 is Arg then X11 is Ser, X16 is Ala, X24 is Ala, X28 is Ala and Z2 is Lys, or a pharmaceutically acceptable salt thereof and with the proviso that if X15 is Asp then X8 is Ser.

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

−

4.

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

0.

4. The GLP-2 analogue of claim 1, wherein said substitution at position X10 is Leu, Nle, or an oxidatively stable Met-replacement amino acid, such as Met(O) or Met(O)₂.

5. The GLP-2 analog of claim 1 which is:

(i) 2263-HGEGSFSDELSTILESLAASDFISWLISTKITD-NH2 (SEQ ID NO;

     7),

(ii) 2264-HGEGSFSDELATILEALAAADFIAWLIATKITD-NH2 (SEQ ID NO;

8),

(iii) 2266-HGEGSFSDELETILEELAAEDFIEWLIETKITD-NH2 (SEQ ID NO;

9),

(iv) 2267-HGEGSFSDELSTILESLAAADFIAWLIATKITD-NH2 (SEQ ID NO;

10),

(v) 2268-HGEGSFSDELATILEALAASDFISWLISTKITD-NH2 (SEQ ID NO;

11),

(vi) 2269-HGEGSFSDELKTILESLAAADFIEWLIQTKITD-NH2 (SEQ ID NO;

12),

(vii) 2270-HGEGSFSDELNTILESLAASDFISWLISTKITD-NH2 (SEQ ID NO;

13),

(viii) 2272-HGEGSFSDELATILESLAAADFISWLIATKITD-NH2 (SEQ ID NO;

14), or

(ix) 2242-HGEGSFSSELSTILDALAARDFIAWLIATKITDK-OH (SEQ ID NO;

15).

6. The GLP-2 analogue of claim 1 which is:

2264 HGEGSFSDELATILEALAAADFIAWLIATKITD-NH₂ (SEQ ID NO;

8).