Lecufexor (D119031166, ID166) is a novel potent, selective farnesoid X receptor (FXR) agonist with EC50 of 3 nM and 5 nM in TR-FRET FXR co-activator assay and FXR reporter assay, respectively.
ID166 induces SHP gene expression more strongly than obeticholic acid (OCA) (EC50 of 1 μM) with an EC50 value of 19 nM in human hepatocytes.
ID166 is highly selective for FXR against a luciferase reporter assay on 19 human nuclear receptors up to 3 μM, also does not exhibit agonistic activities on either MRGPRX4 or TGR5 up to 100 μM.
ID166 strongly increases the gene expression levels of the FXR target genes up to 14-fold in hamster liver and intestine in a dose-dependent manner, and plasma fibroblast growth factor 15 (FGF15) level is significantly increased by ID166 at a dose of 20 mg/kg/day.
ID166 (30 mg/kg) ameliorates the NASH phenotype induced by the fed free choice diet.
ID166 reduces total NAFLD activity and hepatic fibrosis score in NASH hamsters fed a free choice diet, modulates the relative abundance of gut microbes in NASH hamsters.