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 inhibiting the activity of 15-PGDH enzyme, the method comprising:
administering to the enzyme a compound having the following 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, Cl, 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, Cl, 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.
2. The method of claim 1 , wherein the compound has a formula selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
3. The method of claim 1 , wherein the compound has the formula:
and pharmaceutically acceptable salts thereof.
4. The method of claim 1 , wherein the compound has the formula:
and pharmaceutically acceptable salts thereof.
5. The method of claim 1 , wherein the compound has the formula:
and pharmaceutically acceptable salts thereof.
6. The method of claim 1 , wherein the 15-PGDH enzyme is in a tissue of a subject and the compound is administered to the tissue of the subject at an amount effective to increase prostaglandin levels in the tissue.
7. A method for mitigating rejection or enhancing engraftment of a bone marrow graft in a subject recipient of the bone marrow graft, comprising administering to the subject a compound having the following 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, Cl, 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, Cl, 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.
8. The method of claim 7 , where the compound or pharmaceutically acceptable salt thereof is administered to the subject before receipt of the bone marrow graft.
9. The method of claim 7 , where the compound or pharmaceutically acceptable salt thereof is administered to the subject during receipt of the bone marrow graft.
10. The method of claim 7 , where the compound or pharmaceutically acceptable salt thereof is administered to the subject after receipt of the bone marrow graft.
11. The method of claim 7 , wherein the administration occurs following treatment of the subject or the bone marrow of the subject with radiation therapy, chemotherapy, or immunosuppressive therapy.
12. A method for treating colitis in a subject, comprising administering to the subject a compound having the following 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, Cl, 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, Cl, 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.
13. The method of claim 12 , wherein the colitis is ulcerative colitis.
14. A method for promoting liver regeneration following liver surgery or injury in a subject, comprising administering to the subject a compound having the following 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, Cl, 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, Cl, 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.
15. The method of claim 14 , wherein the surgery is liver resection.