Treatment for non-alcoholic fatty liver disease
Inventors
Li, Chiang J. • Derdak, Zoltan • Liu, Jifeng
Assignees
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Publication Number
US-12318381-B2
Publication Date
2025-06-03
Expiration Date
Abstract
The invention provides novel methods of treating or preventing nonalcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH) in a mammal including a human.
Core Innovation
The invention relates to methods for treating and preventing nonalcoholic fatty liver disease (NAFLD) in a mammal by administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt, solvate, ester or pro-drug thereof, together with a pharmaceutically acceptable excipient, carrier, or diluent. The disclosed Formula I includes independently selectable symbols and extensive Markush-style options for ring and substituent groups, with related structural formulas including Formula II-VI and Formula VII and Formula VII-a through Formula VII-j.
The disclosed embodiments also cover reducing or ameliorating a symptom or indication known to be associated with NAFLD. The symptom or indication is selected from accumulation of liver fat, elevated hepatic triglyceride, hepatic fibrosis, hepatocyte ballooning, elevated levels of liver enzymes aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), and an NAFLD Activity Score (NAS) greater than 3.
The composition framework further permits combination administration with additional agents, including vitamins such as vitamin D and vitamin E, and other agent categories such as lipid-lowering, insulin-sensitizing, anti-inflammatory, cholesterol, diabetes, and weight-loss agents. It also allows combination with specified anti-NASH agents, including farnesoid X receptor agonists (FXR agonists), PPAR agonists, acetyl-CoA carboxylase (ACC), C-C chemokine ligands antagonists, ASK1 inhibitors, LOXL2 antibodies, anti-hepatofibrotic agents, and galectin-3 inhibitors.
Claims Coverage
The document includes three independent claims across the provided inputs. The inventive features focus on administering a therapeutically effective amount of a pharmaceutical composition containing a compound of Formula I, including specified stereochemical and derivative forms, together with a pharmaceutically acceptable excipient, carrier, or diluent. The claims define therapeutic scope for treating NAFLD and reducing or ameliorating NAFLD-associated symptoms or indications.
Treating nonalcoholic fatty liver disease by administering a formula I pharmaceutical composition
A method for treating nonalcoholic fatty liver disease (NAFLD) in a mammal by administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt, solvate, ester or pro-drug thereof, together with a pharmaceutically acceptable excipient, carrier, or diluent.
Reducing or ameliorating a nafld-associated symptom or indication by administering a formula I pharmaceutical composition
A method for reducing or ameliorating a symptom or indication known to be associated with NAFLD in a mammal, where the symptom or indication is selected from accumulation of liver fat, elevated hepatic triglyceride, hepatic fibrosis, hepatocyte ballooning, elevated AST and/or ALT, or an NAFLD Activity Score (NAS) greater than 3, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt, solvate, ester or pro-drug thereof, together with a pharmaceutically acceptable excipient, carrier, or diluent.
Formula I pharmaceutical composition for NAFLD treatment
Administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt, solvate, ester or pro-drug thereof, to a mammalian subject in need thereof for treating nonalcoholic fatty liver disease (NAFLD), together with a pharmaceutically acceptable excipient, carrier, or diluent.
The independent claims are directed to administering a therapeutically effective amount of a pharmaceutical composition containing a compound of Formula I, including enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salt/solvate/ester/pro-drug forms, together with a pharmaceutically acceptable excipient/carrier/diluent. The claims cover treating NAFLD and reducing or ameliorating selected NAFLD-associated symptoms or indications.
Stated Advantages
Treats nonalcoholic fatty liver disease (NAFLD) in a mammal.
Reduces or ameliorates a symptom or indication known to be associated with NAFLD, including accumulation of liver fat, elevated hepatic triglyceride, hepatic fibrosis, hepatocyte ballooning, elevated AST and/or ALT, and an NAFLD Activity Score (NAS) greater than 3.
Suppress triglyceride accumulation in HepG2 cells.
Improve NAFLD/NASH outcomes in an HFD-induced murine model, including reduced liver steatosis, inflammation markers, and fibrosis/collagen production.
Reduce NAFLD Activity Score (NAS) and serum ALT/AST.
Modulate fatty-acid oxidation mediators (CPT1a, ACOX1, FGF21) and leptin resistance.
Downregulate adipogenic targets including PPAR-gamma, FABP4, and CD36.
Documented Applications
Methods for treating NAFLD in a mammal, including NAFLD characterized as NASH and NAFLD characterized as simple steatosis.
Methods for reducing or ameliorating NAFLD-associated symptoms or indications selected from accumulation of liver fat, elevated hepatic triglyceride, hepatic fibrosis, hepatocyte ballooning, elevated AST and/or ALT, and NAS greater than 3.
Treatment and prevention of nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis (NASH) and simple steatosis.
Biomedical evaluation of representative compounds, notably Compound 13-3 and deuterated variants, for suppressing intracellular triglyceride accumulation in HepG2 cells.
Use in an HFD-induced murine model to improve NAFLD/NASH outcomes as assessed by liver steatosis, inflammation markers, fibrosis/collagen production, NAFLD Activity Score, serum ALT/AST, and changes in CPT1a, ACOX1, FGF21, leptin, PPAR-gamma, FABP4, and CD36.
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