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 pharmaceutical composition comprising a compound having the formula (V):
or a pharmaceutically acceptable salt thereof;
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 H or NH 2 ;
R 5 is a branched or linear alkyl or
wherein n 2 =0-6 and X is any of the following: CF y H z (y+z=3), CCl y H z (y+z=3), OH, OAc, OMe, CN, or
(n 3 =0-5, m=1-5);
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, carbamide, cyano (—CN), isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C 1 -C 24 alkyl amino, C 1 -C 24 alkyl amino substituted with hydroxyl, 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 thiazole and R 5 is butyl; or R 3 is not an unsubstituted phenyl if R 1 is an unsubstituted thiazole and R 5 is (CH 2 )n 5 (CH 3 )(n 5 =0-5).
2. The composition of claim 1 , wherein R 1 is a substituted or unsubstituted thiazole, oxazole, imidazole, pyrimidine or pyridine.
3. The composition 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 .
4. The composition of claim 1 , wherein the compound has formula (V 1 )
or a pharmaceutically acceptable salt thereof;
wherein n=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 =0-6 and X is any of the following: CF y H z (y+z=3), CCl y H z (y+z=3), OH, OAc, OMe, CN, or
(n 3 =0-5, m=1-5);
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).
5. The composition of claim 4 , 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 .
6. The composition of claim 1 , the compound having a formula selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
7. The composition of claim 1 , the compound having the formula:
or a pharmaceutically acceptable salt thereof.
8. The composition of claim 1 , the compound having the formula:
or a pharmaceutically acceptable salt thereof.
9. The composition of claim 1 , the compound having the formula:
or a pharmaceutically acceptable salt thereof.
10. The composition of claim 1 , the compound consisting essentially of the (+) optical isomer of a compound of the formula:
or a pharmaceutically acceptable salt thereof.
11. The composition of claim 1 , the compound inhibiting the activity of a 15-PGDH enzyme.
12. The composition of claim 1 , wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC 50 of less than 1 μM.
13. The composition of claim 1 , including an amount of the compound effective to increase prostaglandin levels in tissue of a subject when administered to a subject.
14. A compound having the formula:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 having the formula:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 14 having the formula:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 14 consisting essentially of the (+) optical isomer of a compound of the formula:
or a pharmaceutically acceptable salt thereof.
18. The composition of claim 1 , wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC 50 of less than 250 nM.
19. The composition of claim 1 , wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC 50 of less than 50 nM.
20. The composition of claim 1 , wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC 50 of less than 10 nM.
21. The composition of claim 1 , wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC 50 of less than 5 nM.