l-165041 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

Nonalcoholic steatohepatitis (NASH) is considered as severe hepatic manifestation of the metabolic syndrome and has alarming global prevalence. The ligand-activated transcription factors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) δ have been validated as molecular targets to counter NASH. To achieve robust therapeutic efficacy in this multifactorial pathology, combined peripheral PPARδ-mediated activity and hepatic effects of FXR activation appear as a promising multitarget approach. We have designed a minimal dual FXR/PPARδ activator scaffold by rational fusion of pharmacophores derived from selective agonists. Our dual agonist lead compound exhibited weak agonism on FXR and PPARδ and was structurally refined to a potent and balanced FXR/PPARδ activator in a computer-aided fashion. The resulting dual FXR/PPARδ modulator comprises high selectivity over related nuclear receptors and activates the two target transcription factors in native cellular settings.

Topics: Drug Design; Drug Discovery; Humans; Ligands; Molecular Docking Simulation; Non-alcoholic Fatty Liver Disease; PPAR delta; Receptors, Cytoplasmic and Nuclear; Structure-Activity Relationship