Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans

Modification of a gut restricted class of benzimidazole DGAT1 inhibitor <b>1</b> led to <b>9</b> with good oral bioavailability. The key structural changes to <b>1</b> include bioisosteric replacement of the amide with oxadiazole and α,α-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both <b>1</b> and <b>9</b> can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs. Interestingly, only <b>9</b> was found to be effective in suppressing body weight gain relative to control in a diet-induced obese dog model, suggesting the importance of systemic inhibition of DGAT1 for body weight control. <b>9</b> has advanced to clinical investigation and successfully suppressed postprandial triglycerides during an acute meal challenge in humans