1 research outputs found
Discovery of Orally Efficacious Tetrahydrobenzimidazoles as TGR5 Agonists for Type 2 Diabetes
We
have discovered a novel series of tetrahydrobenzimidazoles <b>3</b> 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
EC<sub>50</sub> 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)<sub>0–120 min</sub> in oral glucose tolerance tests
(OGTT)