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

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