Intestinotrophic glucagon-like peptide-2 analogs
AssigneeNPS Allelix Corp.
InventorsDaniel J. Drucker, Anna E. Crivici, Martin Sumner-Smith
Life of this patent
Estimating the term…
Abstract
Analogs of glucagon-like peptide 2, a product of glucagon gene expression, have been identified as intestinal tissue growth factors. Their formulation as pharmaceutical, and therapeutic use in treating disorders of the small bowel, are described.
Claims25
A GLP-2 analog, or a pharmaceutically acceptable salt thereof, which has intestinotrophic activity and which has the formula (SEQ ID NO:
- 1):
- R1-(Y1)m-X1-X2-X3-X4-Ser5-Phe6-Ser7-Asp8-(P1)-Leu14-Asp15-Asn16-Leu17-Ala18-X19-X20-Asp21-Phe22-(P2)-Trp25-Leu26-Ile27-Gln28-Thr29-Lys30-(P3)-(Y2)n-R2,
- wherein:
- X1 is His or Tyr X2 is Ala or an Ala-replacement amino acid which confers on the analog or salt resistance to cleavage by human DPP-IV enzyme;
- X3 is Pro or HPro;
- X4 is Gly or Ala;
- P1 is Glu-X10-Asn-Thr-Ile (SEQ ID NO. 3) or Tyr-Ser- Lys-Tyr (SEQ ID NO. 4);
- X10 is Met or an oxidatively stable Met-replacement amino acid;
- X19 is Ala or Thr;
- X20 is Arg, Lys, His or Ala;
- P2 is Ile-Asn, Ile-Ala or Val-Gln;
- P3 is a covalent bond, or is Ile, Ile-Thr or Ile-Thr-Asp;
- R1 is H or an N-terminal blocking group;
- R2 is OH or a C-terminal blocking group;
- Y1 is one or two amino acids selected from the group consisting of Arg, Lys and His;
- Y2 is one or two amino acids selected from the group consisting of Arg, Lys and His;
- m and n, independently, are 0 or 1
An intestinotrophic analog of a human GLP-2, or a pharmaceutically acceptable salt thereof, wherein the analog or salt has in place of Asp3 either Pro or HPro, and at least one of the following:
- a) in place of Ala2 is an amino acid which confers on the analog or salt resistance to cleavage by human DPP-IV enzyme;
- b) in place of Met10 is an amino acid which is oxidatively stable;
- and
- c) in place of Arg20 is an amino acid other than Arg.
An intestinotrophic GLP-2 analog selected from the group consisting of:
- [Ser2, Gln3]humanGLP-2 (1-33);
- [Gly2, Ala25]humanGLP-2(1-33);
- [Gly2, Ala26]humanGLP-2(1-33);
- [Gly2, Ala14]humanGLP-2(1-33);
- [Gly2, Ala23]humanGLP-2(1-33);
- [Gly2, Ala30]humanGLP-2(1-33);
- [Tyr1, Gly2]humanGLP-2(1-33);
- [Gly2, Arg34]humanGLP-2(1-34);
- [Gly2, Tyr34]humanGLP-2 (1-34);
- [tBuGly2] humanGLP-2;
- [Asp2]humanGLP-2 (1-33);
- [Glu2]humanGLP-2 (1-33);
- [Phe2]humanGLP-2 (1-33);
- [His2]humanGLP-2(1-33);
- [Ile2]humanGLP-2(1-33);
- [Lys2]humanGLP-2(1-33);
- [Met2]humanGLP-2(1-33);
- [Asn2]humanGLP-2 (1-33);
- [Pro2]humanGLP-2(1-33);
- [Gln2]humanGLP-2(1-33);
- [Ser2]humanGLP-2(1-33);
- [Thr2]humanGLP-2(1-33);
- [Val2]humanGLP-2(1-33);
- [Tyr2]humanGLP-2(1-33);
- [D-Ala2]humanGLP-2(1-33);
- [Pen2]humanGLP-2 (1-33);
- [bAla2]humanGLP-2 (1-33);
- [aAbu2]humanGLP-2(1-33);
- [Nval2]humanGLP-2(1-33);
- [PhGly2]humanGLP-2(1-33);
- and
- [Aib2]humanGLP-2(1-33).
An intestinotrophic GLP-2 analog selected from the group consisting of:
- [Asn33]humanGLP-2(1-33);
- [Nle10]ratGLP-2(1-33);
- and
- [Met(O)10]ratGLP-2 (1-33).
An intestinotrophic GLP-2 analog selected from the group consisting of:
- Ac-ratGLP-2(1-33);
- ratGLP-2(1-30);
- ratGLP-2(1-25);
- ratGLP-2(1-33)amide;
- [Arg-2 Arg-1]ratGLP-2 (2-33);
- [Pro1]humanGLP-2 (1-33);
- [Gln20]humanGLP-2(1-33);
- [Asp1]humanGLP-2 (1-33);
- [Tyr34]humanGLP-2 (1-34);
- [desNH2Tyr1]humanGLP-2 (1-33);
- [Thr5]humanGLP-2 (1-33);
- [Ser16 Arg17, Arg18]humanGLP-2(1-33);
- [Agm34]humanGLP-2(1-34);
- [Arg30]humanGLP-2(1-33);
- [Ala5, Ala7]humanGLP-2(1-33);
- [Glu33]humanGLP-2(1-33);
- [Phe25]humanGLP-2(1-33);
- and
- [Tyr25]humanGLP-2(1-33).
Dependencies are inferred from the claim text.