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 and a further treatment for said fatty liver disease, 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 nonalcoholic fatty liver disease (NAFLD).
3. The method of claim 1 , wherein the fatty liver disease is an alcohol related liver disease selected from alcohol fatty liver disease (AFL), alcoholic steatohepatitis (ASH) and 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.
15. The method of claim 1 , wherein said further treatment comprises a lifestyle modification.
16. The method of claim 15 , wherein said lifestyle modification is selected from the group of lifestyle modifications consisting of adoption of a weight loss regimen, caloric restriction, increased exercise, avoidance of alcohol, and avoidance of heptatoxins.
17. The method of claim 1 , wherein said further treatment comprises weight reduction surgery.
18. The method of claim 1 , wherein said further treatment comprises administration of a therapeutic agent selected from the group consisting of propylthiouracil, infliximab, insulin, glucagon, a calcium channel blocker, an antioxidant, S-adenosyl-L-methionine (SAMe), silymarin, and pentoxyfylline.
19. The method of claim 18 , wherein said fatty liver disease is an alcoholic-related fatty liver disease.
20. The method of claim 1 , wherein said further treatment comprises administration of a therapeutic agent selected from the group consisting of a serotonin reuptake inhibitor, sibutramine, orlistat, an insulin-sensitizing agent, a lipid-lowering agent, an antioxidant, a hepatoprotective therapeutic agent, an angiotensin-converting enzyme inhibitor, an angiotensin-receptor blocker, metformin, a monounsaturated fatty acid, a polyunsaturated fatty acid, and combinations thereof.
21. The method of claim 20 , wherein said insulin-sensitizing agent is selected from the group consisting of thiazolidinedione, rosiglitazone, and pioglitazone; said lipid-lowering agent is probucol; said antioxidant is selected from the group consisting of vitamin E, pentoxifylline, betaine and N-acetylcysteine; and said hepatoprotective therapeutic agent is ursodeoxycholic acid.
22. The method of claim 20 , wherein said fatty liver disease is a nonalcoholic fatty liver disease.
23. The method of claim 21 , wherein said fatty liver disease is a nonalcoholic fatty liver disease.