23-substituted bile acids as TGR5 modulators and methods of use thereof
The invention relates to compounds of Formula A: (A) or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. The compounds of Formula A are TGR5 modulators useful for the treatment of various diseases, including obesity, insulin sensitivity, inflammation, cholestasis, and bile desaturation.
1. A compound according to formula A:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydroxy, substituted or unsubstituted alkyl, or halogen;
R 2 is α-hydroxy;
R 3 is hydrogen, hydroxy, NH(CH 2 ) m SO 3 H, or NH(CH 2 ) n CO 2 H;
R 4 is substituted or unsubstituted alkyl, or halogen;
R 5 is unsubstituted or substituted 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 4, 5, or 6 atoms;
R 7 is hydrogen, substituted or unsubstituted alkyl, or hydroxy;
R 8 is hydrogen or substituted or unsubstituted alkyl;
R 9 is hydrogen, substituted or unsubstituted alkyl or taken together R 8 and R 9 form a carbonyl;
R 10 is R 3 or SO 3 H;
m is an integer 0, 1, 2, 3, 4, or 5; and
n is an integer 0, 1, 2, 3, 4, or 5.
2. The compound of claim 1 according to formula I:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is hydroxy, or halogen;
R 2 is α-hydroxy;
R 3 is hydroxy, NH(CH 2 ) m SO 3 H, or NH(CH 2 ) n CO 2 H;
R 4 is unsubstituted or substituted alkyl, or halogen;
R 5 is unsubstituted or substituted alkyl, or aryl;
R 6 is hydrogen or R 5 and R 6 taken together with the carbons to which they are attached form a ring of size 4, 5, or 6 atoms;
m is an integer 0, 1, 2, 3, 4, or 5; and
n is an integer 0, 1, 2, 3, 4, or 5.
3. The compound of claim 1 according to formula IA:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydroxy, substituted or unsubstituted alkyl, or halogen;
R 2 is α-hydroxy;
R 3 is hydroxy, NH(CH 2 ) m SO 3 H, or NH(CH 2 ) n CO 2 H;
R 4 is substituted or unsubstituted alkyl, or halogen;
R 5 is unsubstituted or substituted 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 4, 5, or 6 atoms;
R 7 is hydrogen, or substituted or unsubstituted alkyl, or hydroxy;
m is an integer 0, 1, 2, 3, 4, or 5; and
n is an integer 0, 1, 2, 3, 4, or 5.
4. The compound of claim 1 according to formula II:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydroxy, substituted or unsubstituted alkyl, or halogen;
R 2 is α-hydroxy;
R 4 is hydrogen, substituted or unsubstituted alkyl, or halogen;
R 5 is unsubstituted or substituted 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 4, 5, or 6 atoms;
R 7 is hydrogen, substituted or unsubstituted alkyl, or hydroxy; and
R 8 is hydrogen or substituted or unsubstituted alkyl.
5. The compound of claim 1 , wherein R 6 is hydrogen.
6. The compound of claim 5 , wherein R 1 is hydroxy and R 7 is hydrogen.
7. The compound of claim 6 , wherein R 8 and R 9 taken together form a carbonyl and R 10 is R 3 .
8. The compound of claim 7 , wherein R 3 is hydroxy.
9. The compound of claim 8 , wherein R 5 is unsubstituted alkyl.
10. The compound of claim 9 , wherein R 5 is in the S-configuration.
11. The compound of claim 10 , wherein R 4 is unsubstituted alkyl.
12. The compound of claim 11 , wherein R 4 is methyl or ethyl.
13. The compound of claim 12 , wherein R 4 is ethyl.
14. The compound of claim 1 , wherein R 4 is unsubstituted alkyl.
15. The compound of claim 14 , wherein R 4 is methyl or ethyl.
16. The compound of claim 15 , wherein R 4 is ethyl.
17. A composition comprising the compound of claim 1 or a salt thereof, and at least one pharmaceutically acceptable excipient.
18. A method of ameliorating disease in a subject in need thereof by administering a compound of claim 1 , wherein the disease is selected from obesity, insulin sensitivity, cholestasis, and bile desaturation.
19. A method of ameliorating obesity, or insulin sensitivity in a subject in need thereof by administering a compound according to formula A:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen;
R 2 is α-hydroxy;
R 3 is hydrogen, hydroxy, NH(CH 2 ) m SO 3 H, or NH(CH 2 ) n CO 2 H;
R 4 is hydrogen, substituted or unsubstituted alkyl, or halogen;
R 5 is unsubstituted or substituted 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 4, 5, or 6 atoms;
R 7 is hydrogen, substituted or unsubstituted alkyl, or hydroxy;
R 8 is hydrogen or substituted or unsubstituted alkyl;
R 9 is hydrogen, substituted or unsubstituted alkyl or taken together R 8 and R 9 form a carbonyl; and
R 10 is R 3 or SO 3 H;
m is an integer 0, 1, 2, 3, 4, or 5; and
n is an integer 0, 1, 2, 3, 4, or 5.