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 peptide consisting essentially of the amino acid sequence of any one of SEQ ID NO:1-138. 
     
     
         2 . A pharmaceutical composition in unit dose comprising a guanylate cyclase receptor agonist peptide having the sequence of any one of NO: 1-138 present in a therapeutically effective amount and a pharmaceutical carrier, excipient or diluent. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the unit dose form is selected from the group consisting of a tablet, a capsule, a solution or inhalation formulation. 
     
     
         4 . A method for preventing or treating a condition selected from the group consisting of Ulcerative Colitis, Irritable bowel syndrome (IBS), necrotizing enterocolitis (NEC), non-ulcer dyspepsia chronic intestinal pseudo-obstruction, functional dyspepsia, colonic pseudo-obstruction, duodenogastric reflux, constipation associated with use of opiate pain killers, gastroesophageal reflux disease (GERD), post surgical constipation, gastroparesis, constipation associated with neuropathic disorders, heartburn, poor gastrointestinal motility, congestive heart failure, hypertension, benign prostatic hyperplasia (BPH), colon cancer, lung cancer, bladder cancer, liver cancer, salivary gland cancer or skin cancer, bronchitis, tissue inflammation, organ inflammation, respiratory inflammation, asthma, COPD comprising administering to a patient in need thereof, an effective dosage of a guanylate cyclase receptor agonist having the sequence of any one of NO:1-138. 
     
     
         5 . A method of  claim 4 , further comprising administering an effective dose of inhibitor of a cGMP-specific phosphodiesterase. 
     
     
         6 . The method of  claim 5 , further comprising administering to said patient an effective dose of an inhibitor of cGMP-dependent phosphodiesterase either concurrently or sequentially with said guanylate cyclase receptor agonist. 
     
     
         7 . The method of  claim 5 , wherein said cGMP-dependent phosphodiesterase inhibitor is selected from the group consisting of suldinac sulfone, zaprinast, and motapizone, vardenifil, and suldenifil. 
     
     
         8 . The method of  claim 4 , futher comprising administering an effective does of at least one anti-inflammatory agent. 
     
     
         9 . The method of  claim 8 , wherein an anti-inflammatory agent is a steroid or nonsteroid anti-inflammatory drug (NISAIDS). 
     
     
         10 . The use of any one of the peptides having the sequence of any one of SEQ ID NO:1-131 in the manufacture of a medicament for the treatment of a human disease. 
     
     
         11 . A method of increasing cGMP production in a cell comprising contacting said cell with a peptide selected from the group consisting of the amino acid sequence of SEQ ID NO: 1-138. 
     
     
         12 . The method of  claim 11 , further comprising contacting said cell with a phosphodiesterase inhibitor. 
     
     
         13 . The method of  claim 12 , wherein said cGMP-dependent phosphodiesterase inhibitor is selected from the group consisting of suldinac sulfone, zaprinast, and motapizone, vardenifil, and suldenifil.