Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists

Although several potent bile acid Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1) dual agonists such as INT-767 have been reported, no non-bile acid FXR/TGR5 dual agonist has been investigated to date. Therefore, we attempted to discover potent non-bile acid FXR/TGR5 dual agonists and identified some non-bile acid FXR/TGR5 dual agonists, such as isonicotinamide derivatives in vitro assay. Compound 20p was evaluated in C57BL/6J mice, that were administered a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) consisting of 60 kcal% fat and 0.1% methionine by weight for one week. Compound 20p dose-dependently induced small heterodimer partner (SHP) mRNA and decreased cytochrome P450 7A1 (CYP7A1) in the liver at 10 and 30 mg/kg, respectively, which were used as FXR agonist markers. Compound 20p significantly increased the plasma levels of GLP-1 as a TGR5 agonist, and a high concentration of GLP-1 lowered blood glucose levels. We confirmed that compound 20p was a non-bile acid FXR/TGR5 dual agonist.

Automated summary

Research identified potent non-bile acid FXR/TGR5 dual agonists, such as compound 20p, in vitro and in C57BL/6J mice. Compound 20p demonstrated dose-dependent activation of FXR and TGR5, inducing SHP mRNA and reducing CYP7A1 levels in the liver while increasing plasma GLP-1 levels, resulting in lowered blood glucose levels. This confirmed compound 20p as a non-bile acid FXR/TGR5 dual agonist.