alitretinoin and Non-alcoholic-Fatty-Liver-Disease

A series of fexaramine analogs were synthesized and evaluated to develop an intestine-selective/specific FXR partial agonist. Introduction of both a CN substituent at the C-2 in the biphenyl ring and a fluorine at the C-5 in the aniline ring in fexaramine markedly increased FXR agonistic activity.

Topics: Acrylates; Animals; Bile Acids and Salts; Esters; Intestines; Liver; Mice; Non-alcoholic Fatty Liver Disease; Rats; Receptors, Cytoplasmic and Nuclear

Farnesoid X receptor (FXR) plays a key role in bile acid homeostasis, inflammation, fibrosis, and metabolism of lipid and glucose and becomes a promising therapeutic target for nonalcoholic steatohepatitis (NASH) or other FXR-dependent diseases. The phase III trial results of obeticholic acid demonstrate that the FXR agonists emerge as a promising intervention in patients with NASH and fibrosis, but this bile acid-derived FXR agonist brings severe pruritus and an elevated risk of cardiovascular disease for patients. Herein, we reported our efforts in the discovery of a series of non-bile acid FXR agonists, and 36 compounds were designed and synthesized based on the structure-based drug design and structural optimization strategies. Particularly, compound

Topics: Animals; Binding Sites; Chemical and Drug Induced Liver Injury; Chenodeoxycholic Acid; Drug Design; Drug Evaluation, Preclinical; Half-Life; Humans; Liver; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Non-alcoholic Fatty Liver Disease; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Structure-Activity Relationship