Discovery of new piperidine amide triazolobenzodiazepinones as intestinal-selective CCK1 receptor agonists

New cholecystokinin-1 receptor (CCK1R) agonist ‘triggers’ were identified using iterative library synthesis. Structural activity relationship studies led to the discovery of compound 10e, a potent CCK1R agonist that demonstrated robust weight loss in a diet-induced obese rat model with very low systemic exposure. Pharmacokinetic data suggest that efficacy is primarily driven through activation of CCK1R’s located within the intestinal wall.

Compound 10e was identified as a potent CCK1 receptor agonist (IC50 = 20.3 nM, EC50 = 25.4 nM). Compound 10e demonstrated significant weight loss effects in an obese rat model despite low oral bioavailability (F = 0.13%).Figure optionsDownload as PowerPoint slide