COMPOSITIONS AND METHODS OF MODULATING 15-PGDH ACTIVITY
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.