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 1 led to 9 with good oral bioavailability. The
key structural changes to 1 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 1 and 9 can suppress postprandial triglycerides during
acute oral lipid challenges in rats and dogs. Interestingly, only 9 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. 9 has advanced to clinical investigation and successfully
suppressed postprandial triglycerides during an acute meal challenge
in humans.