TGR5 modulators and methods of use thereof
The invention relates to compounds of Formula 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 method of ameliorating a disease or condition selected from the group consisting of diabetes, insulin resistance, insulin hyposecretion, and pancreatic fatigue in a subject in need thereof, comprising administering to the subject 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 hydrogen or 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 3, 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 R 8 and R 9 taken together form a carbonyl;
R 10 is R 3 or SO 3 H;
m is 0, 1, 2, 3, 4, or 5; and
n is 0, 1, 2, 3, 4, or 5.
2. The method of claim 1 , wherein the disease or condition is diabetes.
3. The method of claim 1 , wherein the disease or condition is insulin resistance.
4. The method of claim 1 , wherein the disease or condition is insulin hyposecretion.
5. The method of claim 1 , wherein the disease or condition is pancreatic fatigue.
6. The method of claim 1 , wherein:
R 1 is hydroxy, substituted or unsubstituted alkyl, or halogen;
R 2 is α-hydroxy;
R 4 is substituted or unsubstituted alkyl, or halogen; and
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.
7. The method of claim 1 , 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 substituted or unsubstituted alkyl, or halogen;
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;
R 7 is hydrogen;
R 8 and R 9 form a carbonyl; and
R 10 is R 3 .
8. The method of claim 1 , 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 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 8 and R 9 form a carbonyl; and
R 10 is R 3 .
9. The method of claim 1 , wherein R 9 is hydrogen and R 10 is SO 3 H.
10. The method of claim 1 , wherein R 6 is hydrogen.
11. The method of claim 10 , wherein R 2 is α-hydroxy.
12. The method of claim 11 , wherein R 1 hydroxy and R 7 is hydrogen.
13. The method of claim 12 , wherein R 8 and R 9 taken together form a carbonyl and R 10 is R 3 .
14. The method of claim 13 , wherein R 3 is hydroxy.
15. The method of claim 14 , wherein R 5 is unsubstituted alkyl.
16. The method of claim 15 , wherein R 5 is in the S-configuration.
17. The method of claim 16 , wherein R 4 is unsubstituted alkyl.