Discovery of a potent, highly selective, and orally efficacious small-molecule activator of the insulin receptor

A series of 3,6-diaryl-2,5-dihydroxybenzoquinones were synthesized and eval uated for their abilities to selectively activate human insulin receptor ty rosine kinase (IRTK). 2,5-Dihydroxy-6-(1-methylindol-3-yl)-3-phenyl-1,4-ben zoquinone (2h) was identified as a potent, highly selective, and orally act ive small-molecule insulin receptor activator. It activated IRTK with an EC 50 of 300 nM and did not induce the activation of closely related receptors (IGFIR, EGFR, and PDGFR) at concentrations up to 30 000 nM. Oral administr ation of the compound to hyperglycemic db/db mice (0.1-10 mg/kg/day) elicit ed substantial to nearly complete correction of hyperglycemia in a dose-dep endent manner. In ob/ob mice, the compound (10 mg/kg) caused significant re duction in hyperinsulinemia. A structurally related compound 2c, inactive i n IRTK assay, failed to affect blood glucose level in db/db mice at equival ent exposure levels. Results from additional studies with compound 2h, aime d at evaluating classical quinone-related phenomena, provided sufficient gr ounds for optimism to allow more extensive toxicologic evaluation.