Fatty liver disease treatment using glucocorticoid and mineralocorticoid receptor antagonists
The present invention provides treatment of fatty liver disease using a class of pyrimidinedione cyclohexyl compounds.
1. A method of treating fatty liver disease, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula Id, thereby treating the fatty liver disease, wherein the compound of Formula Id has the structure:
wherein
each R 1a is independently H, C 1-6 alkyl, halogen, or C 1-6 haloalkyl;
R 2 is H, or C 1-6 alkyl; and
each R 4 is H, C 1-6 alkyl, halogen, or C 1-6 haloalkyl;
or salts or isomers thereof.
2. The method of claim 1 , wherein the fatty liver disease is alcohol related liver disease (ARLD) or nonalcoholic fatty liver disease (NAFLD).
3. The method of claim 2 , wherein the alcohol related liver disease is alcohol fatty liver disease (AFL), alcoholic steatohepatitis (ASH) or alcoholic cirrhosis.
4. The method of claim 2 , wherein the nonalcoholic fatty liver disease is nonalcoholic steatohepatitis (NASH) or nonalcoholic cirrhosis.
5. The method of claim 1 , wherein each R 1a is C 1-6 haloalkyl.
6. The method of claim 1 , wherein each R 1a is independently selected from the group consisting of H, Me, Et, F, Cl, or —CF 3 .
7. The method of claim 1 , wherein each R 1a is —CF 3 .
8. The method of claim 1 , wherein R 2 is H.
9. The method of claim 1 , wherein the compound of Formula Id is selected from the group consisting of:
10. The method of claim 1 , the compound of Formula Id having the formula:
11. The method of claim 1 , wherein said compound of Formula Id is an antagonist of the glucocorticoid receptor.
12. The method of claim 1 , wherein said compound of Formula Id is an antagonist of the mineralocorticoid receptor.
13. The method of claim 1 , wherein said compound of Formula Id inhibits glucocorticoid binding to the glucocorticoid receptor and is an antagonist of the mineralocorticoid receptor.
14. The method of claim 1 , wherein said compound of Formula Id inhibits glucocorticoid binding to the glucocorticoid receptor with an inhibition constant (K i ) of between about 0.0001 nanomolar (nM) to 1000 nM and is an antagonist of the mineralocorticoid receptor.