Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders

Abstract

The invention provides novel guanylate cyclase-C agonist peptides and their use in the treatment of human diseases including gastrointestinal disorders, inflammation or cancer (e.g., a gastrointestinal cancer). The peptides can be administered either alone or in combination with an inhibitor of cGMP-dependent phosphodiesterase. The gastrointestinal disorder may be classified as either irritable bowel syndrome, constipation, or excessive acidity etc. The gastrointestinal disease may be classified as either inflammatory bowel disease or other GI condition, including Crohn's disease and ulcerative colitis, and cancer.

We claim: 
     
         1 . A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising the peptide of SEQ ID NO: 9, wherein said peptide is a (4,12:7,15) bicycle. 
     
     
         2 . The method of  claim 1 , wherein the effective amount is between about 1 mg to 10 mg per dose. 
     
     
         3 . The method of  claim 2 , wherein the composition is administered once daily to the subject. 
     
     
         4 . The method of  claim 1 , the method further comprising administering to the subject a therapeutically effective amount of an inhibitor of cGMP-specific phosphodiesterase (cGMP-PDE). 
     
     
         5 . The method of  claim 4 , wherein the inhibitor of cGMP-PDE is administered concurrently or sequentially to the subject with the composition comprising the peptide of SEQ ID NO: 9. 
     
     
         6 . The method of  claim 4 , wherein the inhibitor of cGMP-PDE comprises at least one of sulindac sulfone, zaprinast, motapizone, vardenafil, or sildenafil. 
     
     
         7 . The method of  claim 5 , wherein the inhibitor of cGMP-PDE comprises sulindac sulfone or zaprinast.