TGR5 modulators and methods of use thereof
The invention relates to compounds of Formula A: (A) or a salt, solvate, or hydrate thereof. The compounds of formula A are TGR5 modulators useful for the treatment of disease.
1. A compound of formula A:
or a salt or solvate thereof, wherein:
R 1 is hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen;
R 2 is hydrogen or α-hydroxy;
R 4 is substituted or unsubstituted alkyl or halogen;
R 5 is hydrogen;
R 6 is hydrogen;
R 7 is hydrogen, substituted or unsubstituted alkyl, or hydroxy;
R 11 is hydroxyl, OSO 3 H, OSO 3 − , OCOCH 3 , OPO 3 H, OPO 3 2− or hydrogen;
R 12 is hydroxyl, OSO 3 H, OSO 3 − , OCOCH 3 , OPO 3 H, OPO 3 2− or hydrogen, or taken together R 11 and R 12 form a carbonyl;
m is 0, 1, or 2;
n is 0 or 1;
o is 0 or 1; and
p is 1,
wherein m+n+o=3.
2. A compound of formula D:
or a salt or solvate thereof, wherein:
R 1 is hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen;
R 2 is hydrogen or α-hydroxy;
R 4 is substituted or unsubstituted alkyl or halogen;
R 7 is hydrogen, substituted or unsubstituted alkyl, or hydroxy;
R 11 is hydroxyl, OSO 3 H, OSO 3 − , OCOCH 3 , OPO 3 H, OPO 3 2− or hydrogen; and
R 12 is hydroxyl, OSO 3 H, OSO 3 − , OCOCH 3 , OPO 3 H, OPO 3 2− or hydrogen, or taken together R 11 and R 12 form a carbonyl.
3. A compound of formula E:
or a salt or solvate thereof, wherein:
R 1 is hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen;
R 2 is hydrogen or α-hydroxyl;
R 4 is hydrogen, substituted or unsubstituted alkyl, or halogen;
R 5 is hydrogen, unsubstituted alkyl, or aryl;
R 6 is hydrogen, unsubstituted or substituted alkyl, or R 5 and R 6 taken together with the carbons to which they are attached form a ring of size 3, 4, 5, or 6 atoms;
R 7 is hydrogen, substituted or unsubstituted alkyl, or hydroxy;
R 11 is hydroxyl, OSO 3 H, OSO 3 − , OCOCH 3 , OPO 3 H, OPO 3 2− or hydrogen;
R 12 is hydroxyl, OSO 3 H, OSO 3 − , OCOCH 3 , OPO 3 H, OPO 3 2− or hydrogen, or taken together R 11 and R 12 form a carbonyl, provided that at least one of R 5 or R 6 is not hydrogen.
4. The compound according to claim 1 or a salt or solvate thereof, wherein R 1 is OH and R 7 is hydrogen.
5. The compound according to claim 4 or a salt or solvate thereof, wherein R 11 is hydroxyl and R 12 is hydrogen.
6. The compound according to claim 5 , wherein R 2 is α-hydroxyl.
7. The compound according to claim 6 , wherein R 4 is unsubstituted alkyl.
8. The compound according to claim 7 , wherein R 4 is ethyl.
9. The compound according to claim 1 or a salt or solvate thereof, wherein R 2 is H.
10. The compound according to claim 1 or a salt or solvate thereof, wherein R 4 is unsubstituted alkyl.
11. A compound selected from
or a salt or solvate thereof.
12. The salt according to claim 11 , that is:
13. The salt according to claim 11 , that is:
14. The compound according to claim 1 , wherein the compound is a pharmaceutically acceptable salt.
15. The compound according to claim 1 , wherein R 2 is α-hydroxyl.
16. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient.
17. A method of ameliorating obesity in a subject comprising administering to the subject a compound of formula A or a pharmaceutically acceptable salt or solvate thereof:
wherein:
R 1 is hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen;
R 2 is hydrogen or α-hydroxy;
R 4 is substituted or unsubstituted alkyl or halogen;
R 5 is hydrogen;
R 6 is hydrogen;
R 7 is hydrogen, substituted or unsubstituted alkyl, or hydroxy;
R 11 is hydroxyl, OSO 3 H, OSO 3 − , OCOCH 3 , OPO 3 H, OPO 3 2− or hydrogen;
R 12 is hydroxyl, OSO 3 H, OSO 3 − , OCOCH 3 , OPO 3 H, OPO 3 2− or hydrogen, or taken together R 11 and R 12 form a carbonyl;
m is 0, 1, or 2;
n is 0 or 1;
o is 0 or 1; and
p is 1,
wherein m+n+o=3.
18. The method according to claim 17 , wherein the compound or pharmaceutical composition is administered to the subject orally, parentally, intravenously, or topically.
19. The method according to claim 17 , wherein the subject is a human.
20. A method of ameliorating obesity in a subject comprising administering to the subject a compound selected from:
or a pharmaceutically salt or solvate thereof.
21. The method according to claim 20 , comprising administering the pharmaceutically acceptable salt: