The present invention provides new uroguanylin derivatives that are useful for the treatment of gastrointestinal disorders. The present invention also provides compositions and methods of treating gastrointestinal disorders and pharmaceutical compositions for accomplishing the same. In some embodime
The present invention provides new uroguanylin derivatives that are useful for the treatment of gastrointestinal disorders. The present invention also provides compositions and methods of treating gastrointestinal disorders and pharmaceutical compositions for accomplishing the same. In some embodiments, these pharmaceutical compositions include oral dosage forms.
대표청구항▼
1. A polypeptide comprising the amino acid sequence: Xaa1-Xaa2-Xaa3-Cys4-Xaa5-Xaa6-Cys7-Xaa8-Xaa9-Xaa10-Ala11-Cys12-Xaa13-Xaa14-Cys15-Xaa16-Xaa17-Xaa18 [SEQ ID NO: 22] whereinXaa1 is Gly, Asn, Pro, Gln, Ser, Thr, Ala, Val, Leu, Ile, Met, Phe, Trp, Tyr or is absent;Xaa2 is Asp, Glu, Gly, His, Asn, Se
1. A polypeptide comprising the amino acid sequence: Xaa1-Xaa2-Xaa3-Cys4-Xaa5-Xaa6-Cys7-Xaa8-Xaa9-Xaa10-Ala11-Cys12-Xaa13-Xaa14-Cys15-Xaa16-Xaa17-Xaa18 [SEQ ID NO: 22] whereinXaa1 is Gly, Asn, Pro, Gln, Ser, Thr, Ala, Val, Leu, Ile, Met, Phe, Trp, Tyr or is absent;Xaa2 is Asp, Glu, Gly, His, Asn, Ser, Gln, Thr or is absent;Xaa3 is Thr, Glu, Asp, or Ser;Xaa5 is P-Ser, P-Thr, P-homo-Ser, 4-hydroxyvaline phosphate, P-homo-Thr, P-Cys or P-TyrXaa6 is Ile or Leu;Xaa8 is Val, Ile, Ala, or Leu;Xaa9 is Asn, Tyr, Phe, or Gln;Xaa10 is Val, Ile, Ala, Leu or Pro;Xaa13 is Ala, Ser or Thr;Xaa14 is Gly or Ala;Xaa16 is Leu, Ile, Phe, Trp, Tyr, or is absent;Xaa17 is Arg, Lys, Ala, Leu, Val, Ile, Ser, Thr, Met, Phe, Trp, Tyr, Asp, Glu, Gln, Asn or is absent; andXaa18 is Arg, Lys, Ala, Leu, Val, Ile, Ser, Thr, Met, Phe, Trp, Tyr, Asp, Glu, Gln, Asn or is absent. 2. The polypeptide according to claim 1, wherein: Xaa1 is Gly, Asn, Pro, Gln, Ser, Thr, or is absent;Xaa2 is Asp, Glu, Gly, His, Asn, Ser, or is absent;Xaa3 is Thr, Glu, or Asp;Xaa5 is P-Ser, P-Thr, P-homo-Ser, 4-hydroxyvaline phosphate, P-homo-Thr, P-Cys or P-TyrXaa6 is Ile or Leu;Xaa8 is Val, Ile, or Ala;Xaa9 is Asn, Tyr, or Phe;Xaa10 is Val, Ile, or Ala;Xaa13 is Ala or Thr;Xaa14 is Gly;Xaa16 is Leu, Phe, Tyr, or is absent;Xaa17 is Arg, Lys, Ala, Leu, Val, Ile, Ser, Thr, Met, Phe, Trp, Tyr, Asp, Glu, Gln, Asn or is absent; andXaa18 is Arg, Lys, Ala, Leu, Val, Ile, Ser, Thr, Met, Phe, Trp, Tyr, Asp, Glu, Gln, Asn or is absent. 3. The polypeptide according to claim 2, wherein: Xaa1 is Pro, Ser, or is absent;Xaa2 is Gly, His, Asn, Ser, or is absent;Xaa3 is Thr;Xaa5 is P-Ser, P-Thr, P-homo-Ser, 4-hydroxyvaline phosphate, P-homo-Thr, P-Cys or P-TyrXaa6 is Ile;Xaa8 is Ala;Xaa9 is Tyr or Phe;Xaa10 is Ala;Xaa13 is Ala or Thr;Xaa14 is Gly;Xaa16 is Leu, Phe, Tyr, or is absent;Xaa17 is Arg, Lys, Ala, Leu, Val, Ile, Ser, Thr, Met, Phe, Trp, Tyr, Asp, Glu, Gln, Asn or is absent; andXaa18 is Arg, Lys, Ala, Leu, Val, Ile, Ser, Thr, Met, Phe, Trp, Tyr, Asp, Glu, Gln, Asn or is absent. 4. The polypeptide according to claim 3, wherein: Xaa1 is Pro, Ser, or is absent;Xaa2 is Gly, His, Asn, Ser, or is absent;Xaa3 is Thr;Xaa5 is P-Ser, P-Thr, P-homo-Ser, 4-hydroxyvaline phosphate, P-homo-Thr, P-Cys or P-TyrXaa6 is Ile;Xaa3 is Ala;Xaa9 is Tyr or Phe;Xaa10 is Ala;Xaa13 is Ala or Thr;Xaa14 is Gly;Xaa16 is Leu, Phe, Tyr, or is absent;Xaa17 is Arg, Lys, Ala, Val, Leu, Ile or is absent; andXaa18 is Arg, Lys, Ala, Val, Leu, Ile or is absent. 5. The polypeptide according to claim 4, wherein: Xaa1 is Gly, Asn, Gln, Thr, or is absent;Xaa2 is Asp, Glu, or is absent;Xaa3 is Glu or Asp;Xaa5 is P-Ser, P-Thr, P-homo-Ser, 4-hydroxyvaline phosphate, P-homo-Thr, P-Cys or P-TyrXaa6 is Leu;Xaa8 is Val or Ile;Xaa9 is Asn;Xaa10 is Val or Ile;Xaa13 is Thr;Xaa14 is Gly;Xaa16 is Leu, Phe, Tyr, or is absent;Xaa17 is Arg, Lys, Ala, Leu, Val, Ile, Ser, Thr, Met, Phe, Trp, Tyr, Asp, Glu, Gln, Asn or is absent; andXaa18 is Arg, Lys, Ala, Leu, Val, Ile, Ser, Thr, Met, Phe, Trp, Tyr, Asp, Glu, Gln, Asn or is absent. 6. The polypeptide according to claim 5, wherein: Xaa1 is Gly, Asn, Gln, Thr, or is absent;Xaa2 is Asp, Glu, or is absent;Xaa3 is Glu or Asp;Xaa5 is P-Ser, P-Thr, P-homo-Ser, 4-hydroxyvaline phosphate, P-homo-Thr, P-Cys or P-TyrXaa6 is Leu;Xaa8 is Val or Ile;Xaa9 is Asn;Xaa10 is Val or Ile;Xaa13 is Thr;Xaa14 is Gly;Xaa16 is Leu, Phe, Tyr, or is absent;Xaa17 is Arg, Lys, Ala, Val, Leu, Ile or is absent; andXaa18 is Arg, Lys, Ala, Val, Leu, Ile or is absent. 7. The polypeptide of claim 1, wherein the polypeptide comprises the amino acid sequence: Pro Gly Thr Cys P-Ser Ile Cys Ala Tyr Ala Ala Cys Thr Gly Cys [SEQ ID NO: 28]. 8. The polypeptide of claim 1, wherein the polypeptide comprises the amino acid sequence: Asn Asp Asp Cys P-Ser Leu Cys Val Asn Val Ala Cys Thr Gly Cys Leu [SEQ ID NO: 29]. 9. The polypeptide of claim 1, wherein the polypeptide comprises the amino acid sequence: Asn Asp Glu Cys P-Ser Leu Cys Val Asn Val Ala Cys Thr Gly Cys Leu [SEQ ID NO: 30]. 10. The polypeptide of claim 1, wherein the carboxy-terminal amino acid is selected from a D-amino acid and an L-amino acid. 11. The polypeptide of claim 1, wherein said carboxy-terminal amino acid is amidated. 12. A method for treating a gastrointestinal disorder, colon cancer, an inflammatory disorder, obesity, congestive heart failure, benign prostatic hyperplasia (BPH), pain, salt retention or fluid retention, comprising administering a composition comprising the polypeptide of claim 1. 13. The method of claim 12 wherein the gastrointestinal disorder is: a gastrointestinal motility disorder, irritable bowel syndrome, constipation predominant irritable bowel syndrome, chronic constipation, a functional gastrointestinal disorder, gastroesophageal reflux disease, duodenogastric reflux, functional heartburn, dyspepsia, functional dyspepsia, nonulcer dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, diverticulitis, or colonic pseudo-obstruction. 14. The method according to claim 13, wherein the gastrointestinal disorder is irritable bowel syndrome. 15. The method according to claim 13, wherein the gastrointestinal disorder is constipation-predominant irritable bowel syndrome. 16. The method according to claim 13, wherein the gastrointestinal disorder is chronic constipation. 17. The method according to claim 13, wherein the gastrointestinal disorder is a gastrointestinal motility disorder. 18. A method for decreasing gastrointestinal pain or visceral pain comprising administering polypeptides of claim 1. 19. A method for increasing the activity of an intestinal guanylate cyclase (GC-C) receptor comprising administering polypeptides of claim 1. 20. A pharmaceutical composition comprising polypeptides of claim 1. 21. The composition of claim 20, wherein said composition is lyophilized.
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Currie, Mark G.; Mahajan-Miklos, Shalina; Fretzen, Angelika; Sun, Li Jing; Norman, Thea; Milne, G. Todd, Methods and compositions for the treatment of gastrointestinal disorders.
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