Discovery of Orally Efficacious Tetrahydrobenzimidazoles as TGR5 Agonists for Type 2 Diabetes.

We have discovered a novel series of tetrahydrobenzimidazoles 3 as TGR5 agonists. Initial structure-activity relationship studies with an assay that measured cAMP levels in murine enteroendocrine cells (STC-1 cells) led to the discovery of potent agonists with submicromolar EC50 values for mTGR5. Subsequent optimization through methylation of the 7-position of the core tetrahydrobenzimidazole ring resulted in the identification of potent agonists for both mTGR5 and hTGR5 (human enteroendocrine NCI-H716 cells). While the lead compounds displayed low to moderate exposure after oral dosing, they significantly reduced blood glucose levels in C57 BL/6 mice at 30 mg/kg and induced a 13-22% reduction in the area under the blood glucose curve (AUC)0-120 min in oral glucose tolerance tests (OGTT).