TGR5 modulators and methods of use thereof
The application relates to compounds of formula A: or a salt, solvate, ester, tautomer, amino acide conjugate, or metabolite thereof. The compounds of formula A are TGR5 modulators useful for the treatment of various diseases, including metabolic disease, inflammatory disease, autoimmune disease, cardiac disease, kidney disease, cancer, and gastrointestinal disease.
1. A method of treating a metabolic disease or disorder in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula A:
or a pharmaceutically acceptable salt, solvate, ester, tautomer, amino acid conjugate, or metabolite thereof, wherein:
A is
oxadiazolonyl, or isoxazolonyl, wherein the carbon atom marked with “*” is bonded to the carbon atom to which A is bonded;
n is 0, 1, or 2;
R 1 is H or OH;
R 2 is H or OH;
R 3 is CR 11 R 12 C(O)OH, C(O)NHR 31 , tetrazolyl, oxadiazolyl, oxadiazolonyl, or thiazolidine-dionyl optionally substituted with NHS(O) 2 —(C 1 -C 3 ) alkyl;
R 11 and R 12 are each independently H, F, OH, CH 2 OH, or CH 2 F, provided that Ru and R 12 are not both H;
R 31 OH, (CH 2 ) p OH, or (CH 2 ) p OSO 3 H; and
p is 1 or 2,
wherein the metabolic disease or disorder is selected from obesity, diabetes, diabesity, metabolic syndrome, insulin resistance, including pre-diabetic insulin resistance, hypertension, and dyslipidemia.
2. The method of claim 1 , wherein A is
3. The method of claim 1 , wherein R 1 and R 2 are each H.
4. The method of claim 1 , wherein R 1 is H, and R 2 is OH.
5. The method of claim 1 , wherein R 2 is H, and R 1 is OH.
6. The method of claim 1 , wherein R 1 and R 2 are each OH.
7. The method of claim 1 , wherein n is 1.
8. The method of claim 1 , wherein R 3 is tetrazolyl, oxadiazolyl, oxadiazolonyl, or thiazolidine-dionyl optionally substituted with NHS(O) 2 -(C 1 -C 3 ) alkyl.
9. The method of claim 1 , wherein the compound is of formula I:
or a pharmaceutically acceptable salt, solvate, ester, tautomer, amino acid conjugate, or metabolite thereof, wherein:
R 11 and R 12 are each independently H, F, OH, CH 2 OH, or CH 2 F, provided that Ru and R 12 are not both H; and
R 13 is H or OH.
10. The method of claim 1 , wherein the compound is of formula II:
or a pharmaceutically acceptable salt, solvate, ester, tautomer, amino acid conjugate, or metabolite thereof, wherein:
q is 0, 1, or 2;
R 21 and R 22 are each independently H or OH; and
R 23 is tetrazolyl, oxadiazolyl, oxadiazolonyl, or thiazolidine-dionyl optionally substituted with NHS(O) 2 -(C 1 -C 3 ) alkyl.
11. The method of claim 10 , wherein the compound of formula II is
12. The method of claim 11 , wherein the compound of formula II is
13. The method of claim 1 , wherein the compound is of formula III:
or a pharmaceutically acceptable salt, solvate, ester, tautomer, amino acid conjugate, or metabolite thereof, wherein:
R 31 is OH, (CH 2 ) p OH, or (CH 2 ) p OSO 3 H; and
p is 1 or 2.
14. A method of treating type II diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula A:
or a pharmaceutically acceptable salt, solvate, ester, tautomer, amino acid conjugate, or metabolite thereof, wherein:
A is
oxadiazolonyl, or isoxazolonyl, wherein the carbon atom marked with “*” is bonded to the carbon atom to which A is bonded;
n is 0, 1, or 2;
R 1 is H or OH;
R 2 is H or OH;
R 3 is CR 11 R 12 C(O)OH, C(O)NHR 31 , tetrazolyl, oxadiazolyl, oxadiazolonyl, or thiazolidine-dionyl optionally substituted with NHS(O) 2 -(C 1 -C 3 ) alkyl;
R 11 and R 12 are each independently H, F, OH, CH 2 OH, or CH 2 F, provided that Ru and R 12 are not both H;
R 31 is OH, (CH 2 ) p OH, or (CH 2 ) p OSO 3 H; and
p is 1 or 2.
15. A method of treating a TGR5-mediated disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula A:
or a pharmaceutically acceptable salt, solvate, ester, tautomer, amino acid conjugate, or metabolite thereof, wherein:
A is
oxadiazolonyl, or isoxazolonyl, wherein the carbon atom marked with “*” is bonded to the carbon atom to which A is bonded;
n is 0, 1, or 2;
R 1 is H or OH;
R 2 is H or OH;
R 3 is CR 11 R 12 C(O)OH, C(O)NHR 31 , tetrazolyl, oxadiazolyl, oxadiazolonyl, or thiazolidine-dionyl optionally substituted with NHS(O) 2 -(C 1 -C 3 ) alkyl;
R 11 and R 12 are each independently H, F, OH, CH 2 OH, or CH 2 F, provided that Ru and Rig are not both H;
R 31 is OH, (CH 2 ) p OH, or (CH 2 ) p OSO 3 H; and
p is 1 or 2.