TGR5 modulators and methods of use thereof
The invention relates to compounds of Formula (A): (A) or a salt, solvate, hydrate, or amino acid conjugate thereof. The compounds of formula A are TGR5 modulators useful for the prevention and treatment of disease.
1. A compound of formula A:
or a salt, solvate, hydrate, or amino acid conjugate thereof, wherein:
R 1 is hydrogen, hydroxyl, substituted or unsubstituted alkyl, or halogen;
R 2 is hydrogen or hydroxyl;
R 4 is substituted or unsubstituted alkyl or halogen;
R 7 is hydrogen, substituted or unsubstituted alkyl, or hydroxyl;
R 11 is hydroxyl, OSO 3 H, OSO 3 − , OCOCH 3 , OPO 3 H, OPO 3 2− , OC 6 H 8 O 6 − , or hydrogen;
R 12 is hydroxyl, OSO 3 H, OSO 3 − , OCOCH 3 , OPO 3 H, OPO 3 2− , OC 6 H 8 O 6 − , or hydrogen, or taken together R 11 and R 12 form a carbonyl; and
R 16 is hydroxyl, alkoxy, or halogen.
2. The compound of claim 1 , wherein the compound is of formula B:
or a salt, solvate, hydrate, or amino acid conjugate thereof.
3. The compound of claim 1 , wherein the compound is of formula C:
or a salt, solvate, hydrate, or amino acid conjugate thereof.
4. The compound of claim 2 , wherein the compound is of formula D:
or a salt, solvate, hydrate, or amino acid conjugate thereof.
5. The compound of claim 1 , wherein the compound is of formula E:
or a salt, solvate, hydrate, or amino acid conjugate thereof.
6. The compound of claim 5 , wherein the compound is of formula F:
or a salt, solvate, hydrate, or amino acid conjugate thereof.
7. A compound, wherein the compound is Compound 10:
or a salt, solvate, hydrate, or amino acid conjugate thereof.
8. The compound of claim 7 , wherein the compound is a pharmaceutically acceptable salt.
9. The compound of claim 1 , wherein the compound is a pharmaceutically acceptable salt.
10. A pharmaceutical composition comprising a compound of claim 1 or a salt, solvate, hydrate, or amino acid conjugate thereof and at least one pharmaceutically acceptable excipient.
11. A method of ameliorating a disease selected from obesity, diabetes, metabolic syndrome, insulin resistance, hypertension, and dyslipidemia, comprising administering the compound of claim 1 or a salt, solvate, hydrate, or amino acid conjugate thereof to a subject in need thereof.
12. The method of claim 1 , wherein the compound or a salt, solvate, hydrate, or amino acid conjugate thereof is administered to a subject orally, parentally, intravenously, or topically.
13. The method of claim 11 , wherein the subject is a human.
14. A pharmaceutical composition comprising a compound of claim 7 or a salt, solvate, hydrate, or amino acid conjugate thereof and at least one pharmaceutically acceptable excipient.
15. A method of ameliorating a disease selected from obesity, diabetes, metabolic syndrome, insulin resistance, hypertension, and dyslipidemia, comprising administering the compound of claim 7 or a salt, solvate, hydrate, or amino acid conjugate thereof to a subject in need thereof.
16. The method of claim 15 , wherein the compound or a salt, solvate, hydrate, or amino acid conjugate thereof is administered to a subject orally, parentally, intravenously, or topically.
17. The method of claim 15 , wherein the subject is a human.