Compositions and methods of modulating short-chain dehydrogenase 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 described herein.
1. A method of inhibiting the activity of a short chain dehydrogenase enzyme of cells or tissue of a subject, the method comprising:
administering to the cells or tissue a compound having the formula (V):
wherein n=1;
R 1 is selected from the group consisting of
R 3 is selected from the group consisting of H, alkyl, —CO 2 H, —CO 2 alkyl, —CONH 2 , —CONH(alkyl), —CON(alkyl) 2 ,
R 2 is N or CH;
R 4 is or NH 2 ;
R 5 is a branched or linear alkyl or
wherein n 2 =1-6 and X is any of the following: CF y H z (y+z=3), CCl y H z (y+z=3), OH, OAc, OMe, or CN;
each R 6 is the same or different and is independently one or more substituent selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl, acyloxy, C 2 -C 24 alkoxycarbonyl, C 6 -C 20 aryloxycarbonyl, C 2 -C 24 alkylcarbonato, C 6 -C 20 arylcarbonato, carboxy, carboxylato, carbamoyl, C 1 -C 24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano(-CN), isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C 1 -C 24 alkyl amino, C 5 -C 20 aryl amino, C 2 -C 24 alkylamido, C 6 -C 20 arylamido, sulfanamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24 alkylsulfanyl, arylsulfanyl, C 1 -C 24 alkylsulfinyl, C 5 -C 20 arylsulfinyl, C 1 -C 24 alkylsulfonyl, C 5 -C 20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkyl ethers, phosphates, phosphate ester, and combinations thereof;
R 3 is not hydrogen if R 1 is an unsubstituted thiophene, or an unsubstituted thiazole and R 5 is butyl; or R 3 is not an unsubstituted phenyl if R 1 is an unsubstituted phenyl, thiophene, or thiazole and R 5 is (CH 2 )n 5 (CH 3 )(n 5 =0-5);
and pharmaceutically acceptable salts thereof.
2. The method of claim 1 , wherein R 1 is a substituted or unsubstituted heterocyclyl containing 5-6 ring atoms.
3. The method of claim 1 , wherein R 1 is a substituted or unsubstituted thiophene, thiazole, oxazole, imidazole, pyridine, or phenyl.
4. The method of claim 1 , wherein R 3 is selected from the group consisting of H, substituted or unsubstituted aryl, cycloalkyl, heterocyclyl, alkyl, —CO 2 H, —CO 2 alkyl, —CONH 2 , —CONH(alkyl), and —CON(alkyl) 2 .
5. The method of claim 1 , wherein the compound has formula (V 1 )
wherein n=0-1;
R 3 is selected from the group consisting of H, alkyl, —CO 2 H, —CO 2 alkyl, —CONH 2 , —CONH(alkyl), —CON(alkyl) 2 ,
R 2 is N or CH;
R 4 is selected from the group consisting of H, and NH 2 ;
R 5 is a branched or linear alkyl or
wherein n 2 =1-6 and X is any of the following: CF y H z (y+z=3), CCl y Hz (y+z=3), OH, OAc, OMe, or CN;
each R 6 is the same or different and is independently one or more substituent selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl, acyloxy, C 2 -C 24 alkoxycarbonyl, C 6 -C 20 aryloxycarbonyl, C 2 -C 24 alkylcarbonato, C 6 -C 20 arylcarbonato, carboxy, carboxylato, carbamoyl, C 1 -C 24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano(-CN), isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C 1 -C 24 alkyl amino, C 5 -C 20 aryl amino, C 2 -C 24 alkylamido, C 6 -C 20 arylamido, sulfanamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24 alkylsulfanyl, arylsulfanyl, C 1 -C 24 alkylsulfinyl, C 5 -C 20 arylsulfinyl, C 1 -C 24 alkylsulfonyl, C 5 -C 20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkyl ethers, phosphates, phosphate ester, and combinations thereof;
R 3 is not hydrogen if R 5 is butyl; or R 3 is not an unsubstituted phenyl if R 5 is (CH 2 )n 5 (CH 3 )(n 5 =0-5);
and pharmaceutically acceptable salts thereof.
6. The method of claim 5 , wherein R 3 is selected from the group consisting of H, substituted or unsubstituted aryl, cycloalkyl, heterocyclyl, alkyl, —CO 2 H, —CO 2 alkyl, —CONH 2 , —CONH(alkyl), and —CON(alkyl) 2 .
7. The method of claim 1 , the compound having a formula selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
8. The method of claim 1 , the compound having the formula:
and pharmaceutically acceptable salts thereof.
9. The method of claim 1 , the compound having the formula:
and pharmaceutically acceptable salts thereof.
10. The method of claim 1 , the compound having the formula:
and pharmaceutically acceptable salts thereof.
11. The method of claim 1 , the compound consisting essentially of the (+) optical isomer of a compound of the formula:
and pharmaceutically acceptable salts thereof.
12. The method of claim 1 , the compound inhibiting the activity of a 15-PGDH enzyme.
13. The method of claim 1 , wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an 10 50 of less than 1 μM.
14. The method of claim 1 , the compound being administered to a tissue of a subject at an amount effective to increase prostaglandin levels in the tissue.
15. The method of claim 1 , the compound being administered to a subject to promote wound healing, tissue repair, and/or tissue regeneration.