Fatty liver disease treatment using glucocorticoid and mineralocorticoid receptor antagonists
Inventors
Belanoff, Joseph K. • Hunt, Hazel • Meijer, Onno C. • van den Heuvel, José
Assignees
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Publication Number
US-12226417-B2
Publication Date
2025-02-18
Expiration Date
Abstract
The present invention provides treatment of fatty liver disease using a class of pyrimidinedione cyclohexyl compounds.
Core Innovation
The invention provides substituted pyrimidine-2,4-dione compounds exemplified as compounds of Formula I and Formula Id, including salts, isomers, solvate, stereoisomers, tautomers, isotopically labeled forms, and prodrugs of the described compounds. The compounds are defined with variable substituents on the core scaffold, including phenyl, halogens, CF3/F/Cl groups, a linker, and substituent patterns defined by R1a, R2, R4, and related Formula Ia to Id variants.
The invention is directed to fatty liver disease treatment, including alcohol-related fatty liver disease (ARLD/AFLD) and nonalcoholic fatty liver disease (NAFLD), and addresses existing therapies described as insufficient. The disclosed compounds are positioned to modulate glucocorticoid receptor and mineralocorticoid receptor activity rather than only GR specificity, with mifepristone referenced in the background and comparative context.
The invention also includes pharmaceutical compositions and formulation options using pharmaceutically acceptable excipients for the disclosed compounds. The document describes assay and experimental examples characterizing GR and MR binding and functional activity for Compound 1, including reporter gene assays, protein:protein interaction assays, and liver lipid data showing reduced lipid droplets or liver fat and triglyceride levels relative to vehicle or mifepristone.
Claims Coverage
The claim coverage centers on one independent method claim and dependent refinements. The independent claim defines oral administration of a therapeutically effective amount of a Formula Id compound for treating fatty liver disease, and the dependent claims add glucocorticoid receptor antagonism, mineralocorticoid receptor antagonism, a Ki range for glucocorticoid binding inhibition, and narrowing to ARLD/NAFLD and specific NAFLD subtypes.
Oral administration of a Formula Id compound for fatty liver disease
Administering to a subject in need thereof a therapeutically effective amount of between 10 mg and 500 mg of a compound of Formula Id, including salts or isomers, by oral administration, with the structure defined by substituents R1a, R2, and R4.
Glucocorticoid receptor antagonism
Using a compound of Formula Id that is an antagonist of the glucocorticoid receptor.
Glucocorticoid binding inhibition constant constraint and mineralocorticoid receptor antagonism
Using a compound of Formula Id that inhibits glucocorticoid binding to the glucocorticoid receptor with a Ki between about 0.0001 nM and 1000 nM and is an antagonist of the mineralocorticoid receptor.
Treatment of ARLD or NAFLD
Treating alcohol-related liver disease (ARLD) or nonalcoholic fatty liver disease (NAFLD).
NAFLD subtype selection
Treating nonalcoholic fatty liver disease selected from nonalcoholic steatohepatitis (NASH) and nonalcoholic cirrhosis.
Defined R1a substituent set
Each R1a is independently selected from H, Me, Et, F, Cl, or —CF3.
Overall, the inventive core centers on oral administration of a therapeutically effective amount of a Formula Id substituted pyrimidine-2,4-dione compound to treat fatty liver disease, with glucocorticoid receptor antagonism and, in narrower forms, mineralocorticoid receptor antagonism, specified Ki constraints, and narrowing of the indication to ARLD/NAFLD and NAFLD subtypes such as NASH and nonalcoholic cirrhosis.
Stated Advantages
Existing therapies for fatty liver disease are described as insufficient.
The disclosed compounds are presented as an alternative treatment approach for fatty liver disease.
The experimental examples report reduced liver lipid droplets, liver fat, and triglyceride levels relative to vehicle or mifepristone.
Documented Applications
Treatment of alcohol-related liver disease (ARLD/AFLD).
Treatment of nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH) and nonalcoholic cirrhosis.
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