Endocrine / Metabolic
Cell culture and mouse studies identified an aminothioimidazole-based GPBAR1 agonist that could help treat insulin resistance. Chemical synthesis and testing of aminothioimidazole analogs in cell-based assays yielded a compound that agonized human and mouse GPBAR1 with EC50 values of 24 and 0.4 nM, respectively. In a mouse model of insulin resistance, the compound increased glucose tolerance and blood levels of the insulin sensitivity-promoting hormone glucagon-like peptide-1 (GLP-1), compared with vehicle. Next steps could include testing the compound in additional models of insulin resistance.
Exelixis Inc. and Bristol-Myers Squibb Co. have TGR5 (XL475), an oral, small molecule agonist of GPBAR1, in preclinical testing to treat metabolic disorders...