The present invention provides pharmaceutical compositions and methods of treating lower gastrointestinal disorders, including irritable bowel syndrome and constipation.
대표청구항▼
1. A method of treating a lower gastrointestinal (GI) disorder in a patient in need thereof or in treating or reducing visceral or abdominal pain or discomfort associated with a GI disorder, comprising administering a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable s
1. A method of treating a lower gastrointestinal (GI) disorder in a patient in need thereof or in treating or reducing visceral or abdominal pain or discomfort associated with a GI disorder, comprising administering a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide comprises the amino acid sequence: Xaa1 Xaa2 Xaa3 Xaa4 Cys5 Xaa6 Xaa7 Xaa8 Cys9 Asn10 Pro11 Ala12 Cys13 Xaa14 Gly15 Xaa16 Xaa17, (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof; whereinXaa1 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 aαaminopimelic acid (Apm);Xaa2 is Asp, β-carboxylated Asp, Glu, γ-carboxylated Glu, Asu, Aad, Apm, or is absent;Xaa3 is Asp, β-carboxylated Asp, Glu, γ-carboxylated Glu, Asu, Aad, Apm, or is absent;Xaa4 is Cys or D-Cys;Xaa6 is Asp or Glu;Xaa7 is Tyr, Leu, Phe or Ile;Xaa8 is Cys or D-Cys;Xaa14 is Thr, Ala or Phe;Xaa16 is Cys or D-Cys; andXaa17 is Tyr, D-Tyr, or is absent;wherein:Xaa1 may be modified on its amino group by methyl, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, hexanedioic acid, heptanedioic acid or octanedioic acid; andif both Xaa2 and Xaa3 are absent, then Xaa1 must be β-carboxylated Asp or γ-carboxylated Glu, or Xaa1 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 method according to claim 1, wherein Xaa2 is Asp or Glu. 3. The method according to claim 1, wherein Xaa2 and Xaa3 are both present. 4. The method according to claim 1, wherein Xaa3 is Asp or Glu. 5. The method according to claim 1, wherein Xaa2 is present and Xaa3 is absent. 6. The method according to claim 1, wherein either or both of Xaa2 and Xaa3 are present and Xaa1 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. 7. The method according to claim 6, wherein Xaa1 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. 8. The method according to claim 1, wherein Xaa2 and Xaa3 are both absent. 9. The method according to claim 1, wherein Xaa6 is Glu. 10. The method according to claim 1, wherein Xaa7 is Tyr or Leu. 11. The method according to claim 1, wherein Xaa4 is Cys and/or Xaa8 is Cys. 12. The method according to claim 1, wherein Xaa14 is Thr. 13. The method according to claim 1, wherein Xaa16 is Cys. 14. The method according to claim 1, wherein Xaa17 is Tyr. 15. The method according to claim 1, wherein Xaa17 is absent. 16. The method according to claim 1, wherein said peptide comprises the amino acid sequence Xaa1 Xaa2 Xaa3 Cys4 Cys5 Glu6 Xaa7 Cys8 Cys9 Asn10 Pro11 Ala12 Cys13 Thr14 Gly15 Cys16 Xaa17 (SEQ ID NO:2); wherein Xaa1 is Asn, D-Asn, Gln, D-Gln, Pro, D-Pro, Ala, βAla, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, Glu or D-Glu;Xaa2 is Asp or Glu;Xaa3 is Asp, Glu, or is absent;Xaa7 is Tyr or Leu; andXaa17 is Tyr or is absent. 17. The method according to claim 16, 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: 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. 18. The method according to claim 17, 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. 19. The method according to claim 1, wherein said peptide comprises the amino acid sequence Xaal Asp2 Xaa3 Cys4 Cys5 Glu6 Xaa7 Cys8 Cys9 Asn10 Pro11 Ala12 Cys13 Thr14 Gly15 Cys16 Xaa17 (SEQ ID NO:68); wherein Xaa1 is Asn, D-Asn, Gln, D-Gln, Pro, D-Pro, Ala, 3-Ala, D-Ala, Val, D-Val, Gly, Thr, D-Thr, Asp, D-Asp, Glu or D-Glu;Xaa3 is Asp or is absent;Xaa7 is Tyr or Leu; andXaa17 is Tyr or is absent. 20. The method 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)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. 21. The method according to claim 1, wherein said peptide comprises no more than 50, 40, 30, 25, 20, 19, 18 or 17 amino acids. 22. The method according to claim 1, wherein said peptide or pharmaceutically acceptable salt thereof is isolated. 23. The method according to claim 22, wherein said peptide or pharmaceutically acceptable salt thereof is purified. 24. The method according to claim 1, wherein said pharmaceutical composition further comprises a pharmaceutically acceptable carrier. 25. The method according to claim 24, wherein said pharmaceutical composition further comprises one or more agents selected from (i) a cation selected from Mg2+, Ca2+, Zn2+, Mn2+, K+, Na+or Al3+, or (ii) a sterically hindered primary amine. 26. The method according to claim 25, said pharmaceutical composition further comprising an antioxidant. 27. The method according to claim 25, said pharmaceutical composition further comprising a pharmaceutically acceptable binder or additive. 28. The method of claim 25, said pharmaceutical composition further comprising a pharmaceutically acceptable filler. 29. The method according to claim 24, said pharmaceutical composition further comprising an additional therapeutic agent. 30. The method according to claim 24 wherein the pharmaceutical composition is administered as a dosage unit. 31. The dosage unit according to claim 30, wherein said dosage unit is a capsule or tablet. 32. The method according to claim 29, wherein said additional therapeutic agent is selected from one or more of an analgesic agent, an antidepressant, a promotility or prokinetic agent, an antispasmodic or an additional therapeutic agent to treat constipation. 33. The method according to claim 1 or 24, wherein said lower GI disorder is selected from impaired lower intestinal mobility, intestinal or colonic pseudo-obstruction, functional bloating, post-operative ileus, irritable bowel syndrome or constipation. 34. The method according to claim 1 or 24, comprising treating or reducing visceral or abdominal pain or discomfort associated with a GI disorder.
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