US2015119328A1PendingUtilityA1
Treatments for Gastrointestinal Disorders
Assignee: IRONWOOD PHARMACEUTICALS INCPriority: Dec 7, 2009Filed: Jan 5, 2015Published: Apr 30, 2015
Est. expiryDec 7, 2029(~3.4 yrs left)· nominal 20-yr term from priority
A61P 3/10A61P 43/00A61P 25/04C07K 7/08A61K 45/06A61P 1/04A61P 1/08A61K 38/10A61K 38/00A61P 1/00A61K 9/0019
45
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Claims
Abstract
Described herein are peptides, compositions, and related methods for treating upper gastrointestinal disorders and conditions (e.g., dyspepsia, gastroparesis, post-operative gastric ileus, a functional esophageal disorder, a functional gastroduodenal disorder, gastroesophageal reflux disease (GERD), or a duodenal or stomach ulcer) as well as other conditions and disorders that are described herein.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid sequence
Xaa 1 Xaa 2 Xaa 3 Xaa 4 Cys 5 Xaa 6 Xaa 7 Xaa 8 Cys 9 Asn 10 Pro 11 Ala n Cys 13 Xaa 14 Gly 15 Xaa 16 Xaa 17 , (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof; wherein Xaa 1 is Asn, D-Asn, Gln, D-Gln, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, β-carboxylated Asp, Glu, D-Glu, γ-carboxylated Glu, α-aminosuberic acid (Asu), α-aminoadipic acid (Aad), or α-aminopimelic acid (Apm); Xaa 2 is Asp, β-carboxylated Asp, Glu, γ-carboxylated Glu, Asu, Aad, Apm, or is absent; Xaa 3 is Asp, β-carboxylated Asp, Glu, γ-carboxylated Glu, Asu, Aad, Apm, or is absent; Xaa 4 is Cys or D-Cys; Xaa 6 is Asp or Glu; Xaa 7 is Tyr, Leu, Phe or Ile; Xaa 8 is Cys or D-Cys; Xaa 14 is Thr, Ala or Phe; Xaa 16 is Cys or D-Cys; and Xaa 17 is Tyr, D-Tyr, or is absent; wherein: Xaa 1 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid; and if both Xaa 2 and Xaa 3 are absent, then Xaa 1 must be β-carboxylated Asp or γ-carboxylated Glu, or Xaa 1 must be Asp, D-Asp, Glu, D-Glu, Asu, Aad, Apm and must be modified on its amino group by ethanedioic acid, propanedioic acid, or butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid.
2 . The peptide or pharmaceutically acceptable salt thereof according to claim 1 , wherein Xaa 2 is Asp or Glu.
3 . The peptide or pharmaceutically acceptable salt thereof according to claim 2 , wherein Xaa 2 is Asp.
4 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 3 , wherein Xaa 2 and Xaa 3 are both present.
5 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 4 , wherein Xaa 3 is Asp or Glu.
6 . The peptide or pharmaceutically acceptable salt thereof according to claim 5 , wherein Xaa 3 is Asp.
7 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 3 , wherein Xaa 2 is present and Xaa 3 is absent.
8 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 3 , and 5 - 6 , wherein either or both of Xaa 2 and Xaa 3 are present and Xaa 1 is Asn, D-Asn, Gln, D-Gln, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, β-carboxylated Asp, Glu, D-Glu, γ-carboxylated Glu, Asu, Aad or Apm.
9 . The peptide or pharmaceutically acceptable salt thereof according to claim 8 , wherein Xaa 1 is Asn, D-Asn, Gln, D-Gln, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, Glu or D-Glu.
10 . The peptide or pharmaceutically acceptable salt thereof according to claim 9 , wherein Xaa 1 is Asp, D-Asp, Glu or D-Glu.
11 . The peptide or pharmaceutically acceptable salt thereof according to claim 1 , wherein Xaa 2 and Xaa 3 are both absent.
12 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 11 , wherein Xaa 6 is Glu.
13 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 12 , wherein Xaa 7 is Tyr or Leu.
14 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 13 , wherein Xaa 4 is Cys and/or Xaa 8 is Cys.
15 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 14 , wherein Xaa 14 is Thr.
16 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 15 , wherein Xaa 16 is Cys.
17 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 16 , wherein Xaa 17 is Tyr.
18 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 16 , wherein Xaa 17 is absent.
19 . The peptide or pharmaceutically acceptable salt thereof according to claim 1 , wherein said peptide comprises the amino acid sequence Xaa 1 Xaa 2 Xaa 3 Cys 4 Cys 5 Glu 6 Xaa 7 Cys 8 Cys 9 Asn 10 Pro 11 Ala 12 Cys 13 Thr 14 Gly 15 Cys 16 Xaa 17 (SEQ ID NO:2); wherein
Xaa 1 is Asn, D-Asn, Gln, D-Gln, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, Glu or D-Glu; Xaa 2 is Asp or Glu; Xaa 3 is Asp, Glu, or is absent; Xaa 7 is Tyr or Leu; and Xaa 17 is Tyr or is absent.
20 . The peptide or pharmaceutically acceptable salt thereof according to claim 19 , wherein said peptide comprises:
(SEQ ID NO: 3)
Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 4)
Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 5)
Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 6)
Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 7)
Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 8)
Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 9)
Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 10)
Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 11)
Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 12)
Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 13)
β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 14)
P-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 15)
Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 16)
Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 17)
β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 18)
β-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 19)
Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 20)
Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 21)
Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 22)
Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 23)
Thr Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 24)
Thr Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 25)
Thr Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 26)
Thr Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 27)
Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 28)
Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 29)
Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 30)
Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 31)
Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 32)
Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 33)
Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 34)
Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 35)
Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 36)
Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 37)
Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 38)
Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 39)
Glu Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 40)
Glu Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 41)
Glu Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 42)
Glu Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 43)
Glu Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 44)
Glu Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 45)
Glu Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
or
(SEQ ID NO: 46)
Glu Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
wherein the C-terminal amino acid residue may be an L-amino acid residue or a D-amino acid residue and if the N-terminal amino acid residue is Asn, Asp, Ala, Pro, Thr or Glu, the N-terminal residue may be an L-amino acid residue or a D-amino acid residue.
21 . The peptide or pharmaceutically acceptable salt thereof according to claim 20 , wherein said peptide comprises:
(SEQ ID NO: 47)
D-Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 48)
D-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 49)
D-Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 50)
D-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 51)
Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys D-Tyr;
(SEQ ID NO: 52)
D-Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 53)
Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 54)
Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 55)
Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 56)
Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 57)
Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 58)
Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 59)
Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 60)
Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 61)
β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 62)
Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 63)
Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 64)
Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 65)
Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 66)
Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
or
(SEQ ID NO: 67)
Glu Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr.
22 . The peptide or pharmaceutically acceptable salt thereof according to claim 1 , wherein said peptide comprises the amino acid sequence Xaa 1 Asp 2 Xaa 3 Cys 4 Cys 5 Glu 6 Xaa 7 Cys 8 Cys 9 Asn 10 Pro 11 Ala 12 Cys 13 Thr 14 Gly 15 Cys 16 Xaa 17 (SEQ ID NO:68); wherein
Xaa 1 is Asn, D-Asn, Gln, D-Gln, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, Glu or D-Glu; Xaa 3 is Asp or is absent; Xaa 7 is Tyr or Leu; and Xaa 17 is Tyr or is absent.
23 . The peptide or pharmaceutically acceptable salt thereof according to claim 22 , wherein said peptide comprises:
(SEQ ID NO: 3)
Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 4)
Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 5)
Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 6)
Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 7)
Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 8)
Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 9)
Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 10)
Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 11)
Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 12)
Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 13)
β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 14)
β-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 15)
Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 16)
Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 17)
β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 18)
β-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 19)
Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 20)
Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 21)
Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 22)
Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 23)
Thr Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 24)
Thr Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 25)
Thr Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 26)
Thr Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 27)
Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 28)
Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 29)
Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 30)
Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 31)
Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 32)
Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 33)
Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 34)
Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 43)
Glu Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 44)
Glu Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 45)
Glu Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
or
(SEQ ID NO: 46)
Glu Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
wherein the C-terminal amino acid residue may be an L-amino acid residue or a D-amino acid residue and if the N-terminal amino acid residue is Asn, Asp, Ala, Pro, Thr or Glu, the N-terminal residue may be an L-amino acid residue or a D-amino acid residue.
24 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 23 , wherein said peptide comprises no more than 50, 40, 30, 25 or 20 amino acids.
25 . The peptide or pharmaceutically acceptable salt thereof according to claim 24 , wherein said peptide comprises no more than 19, 18 or 17 amino acids.
26 . A peptide or a pharmaceutically acceptable salt thereof, wherein the peptide consists of the amino acid sequence
Xaa 1 Xaa 2 Xaa 3 Xaa 4 Cys 5 Xaa 6 Xaa 7 Xaa 8 Cys 9 Asn 10 Pro 11 Ala 12 Cys 13 Xaa 14 Gly 15 Xaa 16 Xaa 17 (SEQ ID NO:1), or a pharmaceutically acceptable salt thereof; wherein Xaa 1 is Asn, D-Asn, Gln, D-Gln, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, β-carboxylated Asp, Glu, D-Glu, γ-carboxylated Glu, α-aminosuberic acid (Asu), α-aminoadipic acid (Aad), or α-aminopimelic acid (Apm); Xaa 2 is Asp, β-carboxylated Asp, Glu, γ-carboxylated Glu, Asu, Aad, Apm, or is absent; Xaa 3 is Asp, β-carboxylated Asp, Glu, γ-carboxylated Glu, Asu, Aad, Apm, or is absent; Xaa 4 is Cys or D-Cys; Xaa 6 is Asp or Glu; Xaa 7 is Tyr, Leu, Phe or Ile; Xaa 8 is Cys or D-Cys; Xaa 14 is Thr, Ala or Phe; Xaa 16 is Cys or D-Cys; and Xaa 17 is Tyr, D-Tyr, or is absent; wherein: Xaa 1 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid; and if both Xaa 2 and Xaa 3 are absent, then Xaa 1 must be β-carboxylated Asp or γ-carboxylated Glu, or Xaa 1 must be Asp, D-Asp, Glu, D-Glu, Asu, Aad, Apm and must be modified on its amino group by ethanedioic acid, propanedioic acid, or butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid.
27 . The peptide or pharmaceutically acceptable salt thereof according to claim 26 , wherein Xaa 2 is Asp or Glu.
28 . The peptide or pharmaceutically acceptable salt thereof according to claim 27 , wherein Xaa 2 is Asp.
29 . The peptide or pharmaceutically acceptable salt thereof according to claim any one of claims 26 - 28 , wherein Xaa 2 and Xaa 3 are both present.
30 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 26 - 29 , wherein Xaa 3 is Asp or Glu.
31 . The peptide or pharmaceutically acceptable salt thereof according to claim 30 , wherein Xaa 3 is Asp.
32 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 26 - 28 , wherein Xaa 2 is present and Xaa 3 is absent.
33 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 26 - 28 and 30 - 31 , wherein either or both of Xaa 2 and Xaa 3 are present and Xaa 1 is Asn, D-Asn, Gln, D-Gln, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, β-carboxylated Asp, Glu, D-Glu, γ-carboxylated Glu, Asu, Aad or Apm.
34 . The peptide or pharmaceutically acceptable salt thereof according to claim 33 , wherein Xaa 1 is Asn, D-Asn, Gln, D-Gln, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, Glu or D-Glu.
35 . The peptide or pharmaceutically acceptable salt thereof according to claim 34 , wherein Xaa 1 is Asp, D-Asp, Glu or D-Glu.
36 . The peptide or pharmaceutically acceptable salt thereof according to claim 26 , wherein Xaa 2 and Xaa 3 are both absent.
37 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 26 - 36 , wherein Xaa 6 is Glu.
38 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 26 - 37 , wherein Xaa 7 is Tyr or Leu.
39 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 26 - 38 , wherein Xaa 4 is Cys and/or Xaa 8 is Cys.
40 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 26 - 39 , wherein Xaa 14 is Thr.
41 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 26 - 40 , wherein Xaa 16 is Cys.
42 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 26 - 41 , wherein Xaa 17 is Tyr.
43 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 26 - 42 , wherein Xaa 17 is absent.
44 . The peptide or pharmaceutically acceptable salt thereof according to claim 26 , wherein said peptide consists of the amino acid sequence Xaa 1 Xaa 2 Xaa 3 Cys 4 Cys 5 Glu 6 Xaa 7 Cys 8 Cys 9 Asn 10 Pro 11 Ala 12 Cys 13 Thr 14 Gly 15 Cys 16 Xaa 17 (SEQ ID NO:2); wherein
Xaa 1 is Asn, D-Asn, Gln, D-Gln, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, Glu or D-Glu; Xaa 2 is Asp or Glu; Xaa 3 is Asp, Glu, or is absent; Xaa 7 is Tyr or Leu; and Xaa 17 is Tyr or is absent.
45 . The peptide or pharmaceutically acceptable salt thereof according to claim 44 , wherein said peptide consists of:
(SEQ ID NO: 3)
Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 4)
Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 5)
Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 6)
Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 7)
Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 8)
Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 9)
Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 10)
Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 11)
Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 12)
Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 13)
β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 14)
β-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 15)
Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 16)
Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 17)
β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 18)
β-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 19)
Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 20)
Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 21)
Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 22)
Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 23)
Thr Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 24)
Thr Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 25)
Thr Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 26)
Thr Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 27)
Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 28)
Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 29)
Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 30)
Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 31)
Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 32)
Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 33)
Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 34)
Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 35)
Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 36)
Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 37)
Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 38)
Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 39)
Glu Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 40)
Glu Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 41)
Glu Glu Glu Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 42)
Glu Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 43)
Glu Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 44)
Glu Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 45)
Glu Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
or
(SEQ ID NO: 46)
Glu Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
wherein the C-terminal amino acid residue may be an L-amino acid residue or a D-amino acid residue and if the N-terminal amino acid residue is Asn, Asp, Ala, Pro, Thr or Glu, the N terminal residue may be an L-amino acid residue or a D-amino acid residue.
46 . The peptide or pharmaceutically acceptable salt thereof according to claim 45 , wherein said peptide comprises:
(SEQ ID NO: 47)
D-Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro
Ala Cys Thr Gly Cys Tyr;
(SEQ ID NO: 48)
D-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro
Ala Cys Thr Gly Cys Tyr;
(SEQ ID NO: 49)
D-Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro
Ala Cys Thr Gly Cys Tyr;
(SEQ ID NO: 50)
D-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro
Ala Cys Thr Gly Cys Tyr;
(SEQ ID NO: 51)
Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys D-Tyr;
(SEQ ID NO: 52)
D-Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro
Ala Cys Thr Gly Cys;
(SEQ ID NO: 53)
Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 54)
Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 55)
Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 56)
Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 57)
Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 58)
Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 59)
Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 60)
Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 61)
β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 62)
Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 63)
Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 64)
Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 65)
Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 66)
Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
or
(SEQ ID NO: 67)
Glu Glu Glu Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr.
47 . The peptide or pharmaceutically acceptable salt thereof according to claim 26 , wherein said peptide consists of the amino acid sequence Xaa 1 Asp 2 Xaa 3 Cys 4 Cys 5 Glu 6 Xaa 7 Cys 8 Cys 9 Asn 10 Pro 11 Ala 12 Cys 13 Thr 14 Gly 15 Cys 16 Xaa 17 (SEQ ID NO. 68); wherein
Xaa 1 is Asn, D-Asn, Gln, D-Gln, Pro, D-Pro, Ala, β-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, Glu, or D-Glu; Xaa 3 is Asp or is absent; Xaa 7 is Tyr or Leu; and Xaa 17 is Tyr or is absent.
48 . The peptide or pharmaceutically acceptable salt thereof according to claim 47 , wherein said peptide consists of:
(SEQ ID NO: 3)
Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 4)
Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 5)
Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 6)
Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
(SEQ ID NO: 7)
Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 8)
Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 9)
Asn Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 10)
Asn Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 11)
Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 12)
Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 13)
β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 14)
β-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 15)
Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 16)
Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 17)
β-Ala Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 18)
β-Ala Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 19)
Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 20)
Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 21)
Pro Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 22)
Pro Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 23)
Thr Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 24)
Thr Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 25)
Thr Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 26)
Thr Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 27)
Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 28)
Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 29)
Gly Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 30)
Gly Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 31)
Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 32)
Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys;
(SEQ ID NO: 33)
Asp Asp Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 34)
Asp Asp Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala
Cys Thr Gly Cys Tyr;
(SEQ ID NO: 43)
Glu Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 44)
Glu Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys;
(SEQ ID NO: 45)
Glu Asp Cys Cys Glu Leu Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
or
(SEQ ID NO: 46)
Glu Asp Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys
Thr Gly Cys Tyr;
wherein the C-terminal amino acid residue may be an L-amino acid residue or a D-amino acid residue and if the N-terminal amino acid residue is Asn, Asp, Ala, Pro, Thr or Glu, the N-terminal residue may be an L-amino acid residue or a D-amino acid residue.
49 . The peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 48 , wherein said peptide or pharmaceutically acceptable salt thereof is isolated.
50 . The peptide or pharmaceutically acceptable salt thereof according to claim 49 , wherein said peptide or pharmaceutically acceptable salt thereof is purified.
51 . A pharmaceutical composition comprising a peptide or pharmaceutically acceptable salt thereof according to any one of claims 1 - 50 .
52 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a peptide according to any one of claims 1 - 50 and one or more agents selected from (i) a cation selected from Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + or Al 3+ , or (ii) a sterically hindered primary amine.
53 . The pharmaceutical composition according to claim 52 , wherein said agent is Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + or Al 3+ .
54 . The pharmaceutical composition according to claim 52 or 53 , wherein said Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + or Al 3+ is provided as magnesium acetate, magnesium chloride, magnesium phosphate, magnesium sulfate, calcium acetate, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, zinc chloride, zinc phosphate, zinc sulfate, manganese acetate, manganese chloride, manganese phosphate, manganese sulfate, potassium acetate, potassium chloride, potassium phosphate, potassium sulfate, sodium acetate, sodium chloride, sodium phosphate, sodium sulfate, aluminum acetate, aluminum chloride, aluminum phosphate or aluminum sulfate.
55 . The pharmaceutical composition according to claim 52 , wherein said agent is a sterically hindered primary amine.
56 . The pharmaceutical composition according to claim 55 , wherein the sterically hindered primary amine is an amino acid.
57 . The pharmaceutical composition according to claim 56 , wherein the amino acid is a naturally occurring amino acid, a non-naturally occurring amino acid or an amino acid derivative.
58 . The pharmaceutical composition according to claim 57 , wherein the naturally occurring amino acid is histidine, phenylalanine, alanine, glutamic acid, aspartic acid, glutamine, leucine, methionine, asparagine, tyrosine, threonine, isoleucine, tryptophan, glycine, or valine or the non-naturally occurring amino acid is 1-aminocyclohexane carboxylic acid, lanthanine or theanine.
59 . The pharmaceutical composition according to claim 52 , wherein the sterically hindered primary amine has the formula:
wherein R 1 , R 2 and R 3 are independently selected from: H, C(O)OH, C 1 -C 6 alkyl, C 1 -C 6 alkylether, C 1 -C 6 alkylthioether, C 1 -C 6 alkyl carboxylic acid, C 1 -C 6 alkyl carboxylamide and alkylaryl, wherein any group can be singly or multiply substituted with: halogen or amino, and provided that no more than one of R 1 , R 2 and R 3 is H.
60 . The pharmaceutical composition according to claim 59 , wherein the sterically hindered primary amine is cyclohexylamine or 2-methylbutylamine.
61 . The pharmaceutical composition according to claim 52 , wherein the sterically hindered primary amine is a polymeric amine.
62 . The pharmaceutical composition according to claim 61 , wherein the polymeric amine is chitosan.
63 . The pharmaceutical composition according to any one of claims 55 - 62 , wherein said pharmaceutical composition further comprises Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + or Al 3+ .
64 . The pharmaceutical composition according to claim 63 , wherein said Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na + or Al 3+ is provided as magnesium acetate, magnesium chloride, magnesium phosphate, magnesium sulfate, calcium acetate, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, zinc chloride, zinc phosphate, zinc sulfate, manganese acetate, manganese chloride, manganese phosphate, manganese sulfate, potassium acetate, potassium chloride, potassium phosphate, potassium sulfate, sodium acetate, sodium chloride, sodium phosphate, sodium sulfate, aluminum acetate, aluminum chloride, aluminum phosphate or aluminum sulfate.
65 . The pharmaceutical composition according to any one of claims 52 - 64 , further comprising an antioxidant.
66 . The pharmaceutical composition according to claim 65 , wherein said antioxidant is BHA, vitamin E or propyl gallate.
67 . The pharmaceutical composition according to any one of claims 52 - 66 , further comprising a pharmaceutically acceptable binder or additive.
68 . The pharmaceutical composition according to claim 67 wherein the pharmaceutically acceptable binder or additive is selected from polyvinyl alcohol, polyvinylpyrrolidone (povidone), a starch, maltodextrin or a cellulose ether.
69 . The pharmaceutical composition according to claim 68 , wherein the pharmaceutically acceptable binder or additive is polyvinyl alcohol.
70 . The pharmaceutical composition of claim 69 wherein the pharmaceutically acceptable binder or additive is a cellulose ether.
71 . The pharmaceutical composition of claim 70 wherein the cellulose ether is selected from: methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
72 . The pharmaceutical composition of any of claims 52 - 71 , further comprising a pharmaceutically acceptable filler.
73 . The pharmaceutical composition according to claim 72 , wherein the pharmaceutically acceptable filler is cellulose, isomalt, mannitol or dibasic calcium phosphate.
74 . The pharmaceutical composition of claim 73 wherein the cellulose is selected from microfine cellulose and microcrystalline cellulose.
75 . The pharmaceutical composition according to any one of claims 51 - 74 , further comprising an additional therapeutic agent.
76 . The pharmaceutical composition according to claim 75 , wherein said additional therapeutic agent is selected from one or more of an analgesic agent, an antidepressant, a promotility or prokinetic agent, an antiemetic, an antibiotic, a proton pump inhibitor, an acid blocker, a PDE5 inhibitor, an acid pump antagonist, a GABA-B agonist, a bile acid sequestrant or a mucosal protecting agent.
77 . A dosage unit comprising the pharmaceutical composition according to any one of claims 51 - 76 .
78 . The dosage unit according to claim 77 , wherein said dosage unit is a capsule or tablet.
79 . The dosage unit according to claim 78 , wherein each of said dosage units comprises 5 μg to 1 mg of said peptide.
80 . A method for treating a gastrointestinal disorder comprising administering the pharmaceutical composition according to any one of claims 51 - 79 .
81 . The method according to claim 80 , wherein said gastrointestinal disorder is gastroparesis, post-operative gastric ileus, a functional esophageal disorder, a functional gastroduodenal disorder, gastroesophageal reflux disease (GERD), celiac disease, mucositis, or a duodenal or stomach ulcer.
82 . The method according to claim 81 , wherein said gastrointestinal disorder is gastroparesis.
83 . The method according to claim 82 , wherein said gastroparesis is idiopathic, diabetic or post-surgical gastroparesis.
84 . The method according to claim 81 , wherein said gastrointestinal disorder is post-operative gastric ileus.
85 . The method according to claim 81 , wherein said gastrointestinal disorder is a functional esophageal disorder.
86 . The method according to claim 85 , wherein said functional esophageal disorder is functional heartburn, functional chest pain of presumed esophageal origin, functional dysphagia or globus.
87 . The method according to claim 81 , wherein said gastrointestinal disorder is a functional gastroduodenal disorder.
88 . The method according to claim 87 , wherein said functional gastroduodenal disorder is functional dyspepsia, a belching disorder, a nausea or vomiting disorder, or rumination syndrome.
89 . The method according to claim 88 , wherein said functional dyspepsia is postprandial distress syndrome or epigastric pain syndrome.
90 . The method according to claim 88 , wherein said belching disorder is aerophagia or unspecified excessive belching.
91 . The method according to claim 88 , wherein said nausea or vomiting disorder is chronic idiopathic nausea, functional vomiting or cyclic vomiting syndrome.
92 . The method according to claim 81 , wherein said gastrointestinal disorder is gastroesophageal reflux disease (GERD).
93 . The method according to claim 81 , wherein said gastrointestinal disorder is a duodenal or stomach ulcer.Join the waitlist — get patent alerts
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