Inhibition ofaeyl-CoA:diaeyiglycerol acyltransferase-1 (DGAT-1), an enzyme that catalyzes the final committed step of triglyceride synthesis, represents a potential therapeutic entry point forthe treatment of diabetes and obesity.In addition to reduced triglyceride levels, DGAT-1 knockout mice exhibit increased insulin/leptin sensitivity and are resistant to diet-induced obesity.This talk will detail the discovery, safety derisking strategies and preclinical pharmacology profile of the potent DGAT-1 inhibitor PF-046201 10, which has entered Phase Ⅰ studies for the treatment of Type-2 diabetes.