Compositions and methods of modulating 15-pgdh activity

Abstract

Compounds and methods of modulating 15-PGDH activity, modulating tissue prostaglandin levels, treating disease, diseases disorders, or conditions in which it is desired to modulate 15-PGDH activity and/or prostaglandin levels include 15-PGDH inhibitors and 15-PGDH activators described herein.

1 . A method of treating gastrointestinal diseases associated with inflammation in a subject in need thereof, the method comprising:
 administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor;   wherein the 15-PGDH inhibitor comprises a compound having formula (III):   
       
         
           
           
               
               
           
         
         wherein n is 1 or 2; 
         R 1  is a C 1-8  alkyl, which is linear, branched, or cyclic and which is unsubstituted or substituted; 
         R 2  and R 3  are the same or different and are each selected from the group consisting of a H, a lower alkyl group, (CH 2 ) n1 OR′, CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 X, CN, (C═O)—R′, (C═O)N(R′) 2 , O(CO)R′, COOR′; 
         Z 1  is S; 
         X 2  is N or C; 
         R 6  and R 7  are optional and if present are the same or different and are each selected from the group consisting of a H, F, Cl, Br, I, a lower alkyl group, (CH 2 ) n1 OR′, CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 X, CN, (C═O)—R′, N(R′) 2 , NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′; substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl; or a pharmaceutically acceptable salt thereof; 
         wherein, where present, each instance of n1 is 1, 2, or 3; 
         wherein, where present, each instance of X is F, Cl, Br, or I; 
         wherein, where present, each instance of R′ is H or a lower alkyl group. 
       
     
     
         2 . The method of  claim 1 , wherein the ulcer comprises at least one of a mucosal or submucosal ulcer. 
     
     
         3 . The method of  claim 1 , wherein the gastrointestinal disease comprises at least one of oral ulcers or gastrointestinal ulcers. 
     
     
         4 . The method of  claim 1 , wherein the gastrointestinal disease comprises at least one of colitis, gastritis, or cryptitis. 
     
     
         5 . The method of  claim 1 , wherein the gastrointestinal disease comprises ulcerative colitis. 
     
     
         6 . The method of  claim 1 , wherein the gastrointestinal disease comprises inflammatory bowel disease. 
     
     
         7 . The method of  claim 1 , wherein the 15-PGDH inhibitor is administered at an amount effective to increase prostaglandin levels in blood or tissue of the subject. 
     
     
         8 . The method of  claim 1 , wherein the 15-PGDH inhibitor is administered to the subject at an amount effective to inhibit or treat at least one of oral or gastrointestinal ulcer formation. 
     
     
         9 . The method of  claim 1 , wherein the 15-PGDH inhibitor is administered to the subject at an amount effective to inhibit or treat at least one of oral or gastrointestinal inflammation. 
     
     
         10 . A method of treating gastrointestinal inflammation, ulcers, or both in a subject in need thereof, the method comprising:
 administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor;   wherein the 15-PGDH inhibitor comprises a compound having formula (III):   
       
         
           
           
               
               
           
         
         wherein n is 1 or 2; 
         R 1  is a C 1-8  alkyl, which is linear, branched, or cyclic and which is unsubstituted or substituted; 
         R 2  and R 3  are the same or different and are each selected from the group consisting of a H, a lower alkyl group, (CH 2 ) n1 OR′, CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 X, CN, (C═O)—R′, (C═O)N(R′) 2 , O(CO)R′, COOR′; 
         Z 1  is S; 
         X 2  is N or C; 
         R 6  and R 7  are optional and if present are the same or different and are each selected from the group consisting of a H, F, Cl, Br, I, a lower alkyl group, (CH 2 ) n1 OR′, CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 X, CN, (C═O)—R′, N(R′) 2 , NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′; substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl; or a pharmaceutically acceptable salt thereof; 
         wherein, where present, each instance of n1 is 1, 2, or 3; 
         wherein, where present, each instance of X is F, Cl, Br, or I; 
         wherein, where present, each instance of R′ is H or a lower alkyl group. 
       
     
     
         11 . The method of  claim 10 , wherein the subject has gastrointestinal ulcers. 
     
     
         12 . The method of  claim 10 , wherein the subject has at least one of colitis, gastritis, or cryptitis. 
     
     
         13 . The method of  claim 10 , wherein the subject has inflammatory bowel disease. 
     
     
         14 . The method of  claim 10 , wherein the 15-PGDH inhibitor is administered at an amount effective to increase prostaglandin levels in blood or tissue of the subject. 
     
     
         15 . The method of  claim 10 , wherein the 15-PGDH inhibitor is administered to the subject at an amount effective to inhibit or treat gastrointestinal ulcer formation. 
     
     
         16 . The method of  claim 10 , wherein the 15-PGDH inhibitor is administered to the subject at an amount effective to inhibit or treat gastrointestinal inflammation. 
     
     
         17 . A method of treating gastrointestinal diseases in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.