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 - 81 . (canceled) 
     
     
         82 : A method of treating oral and/or gastrointestinal diseases associated with inflammation and/or ulcers in a subject in need thereof, the method comprising:
 administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.   
     
     
         83 : The method of  claim 82 , wherein the ulcer comprises at least one of a mucosal or submucosal ulcer. 
     
     
         84 : The method of  claim 82 , wherein the gastrointestinal disease comprises at least one of oral ulcers or gastrointestinal ulcers. 
     
     
         85 : The method of  claim 82 , wherein the gastrointestinal disease comprises at least one of colitis, gastritis, or cryptitis. 
     
     
         86 : The method of  claim 82 , wherein the gastrointestinal disease comprises ulcerative colitis. 
     
     
         87 : The method of  claim 82 , wherein the gastrointestinal disease comprises inflammatory bowel disease. 
     
     
         88 : The method of  claim 82  wherein the 15-PGDH inhibitor is administered at an amount effective to increase prostaglandin levels in blood or tissue of the subject 
     
     
         89 : The method of  claim 82 , wherein the 15-PGDH inhibitor is administered to the subject at an amount effective to inhibit or treat at least one of oral or gastrointesintal ulcer formation. 
     
     
         90 : The method of  claim 82 , wherein the 15-PGDH inhibitor is administered to the subject at an amount effective to inhibit or treat at least one of oral or gastrointesintal inflammation. 
     
     
         91 : The method of  claim 82 , 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′ (wherein n1=1, 2, or 3), 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 (wherein X═F, C, Br, or I), CN, (C═O)—R′, (C═O)N(R′) 2 , O(CO)R′, COOR′ (wherein R′ is H or a lower alkyl group); 
         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′ (wherein n1=1, 2, or 3), 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 (wherein X═F, C, Br, or I), CN, (C═O)—R′, N(R′) 2 , NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′ (wherein R′ is H or a lower alkyl group); substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl; or a pharmaceutically acceptable salt thereof. 
       
     
     
         92 : A method of treating oral and/or gastrointestinal inflammation and/or ulcers in a subject in need thereof, the method comprising:
 administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.   
     
     
         93 : The method of  claim 92 , wherein the subject has at least one of oral ulcers or gastrointestinal ulcers. 
     
     
         94 : The method of  claim 92 , wherein the subject has at least one of colitis, gastritis, or cryptitis. 
     
     
         95 : The method of  claim 92 , wherein the subject has ulcerative colitis. 
     
     
         96 : The method of  claim 92 , wherein the subject has inflammatory bowel disease. 
     
     
         97 : The method of  claim 92  wherein the 15-PGDH inhibitor is administered at an amount effective to increase prostaglandin levels in blood or tissue of the subject 
     
     
         98 : The method of  claim 92 , wherein the 15-PGDH inhibitor is administered to the subject at an amount effective to inhibit or treat at least one of oral or gastrointesintal ulcer formation. 
     
     
         99 : The method of  claim 92 , wherein the 15-PGDH inhibitor is administered to the subject at an amount effective to inhibit or treat at least one of oral or gastrointesintal inflammation. 
     
     
         100 : The method of  claim 92 , 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′ (wherein n1=1, 2, or 3), 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 (wherein X═F, C, Br, or I), CN, (C═O)—R′, (C═O)N(R′) 2 , O(CO)R′, COOR′ (wherein R′ is H or a lower alkyl group); 
         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′ (wherein n1=1, 2, or 3), 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 (wherein X═F, C, Br, or I), CN, (C═O)—R′, N(R′) 2 , NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′ (wherein R′ is H or a lower alkyl group); substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl; or a pharmaceutically acceptable salt thereof.