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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

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posted on 12.05.2017, 00:00 by Katsumasa Nakajima, Ricardo Chatelain, Kevin B. Clairmont, Renee Commerford, Gary M. Coppola, Thomas Daniels, Cornelia J. Forster, Thomas A. Gilmore, Yongjin Gong, Monish Jain, Aaron Kanter, Youngshin Kwak, Jingzhou Li, Charles D. Meyers, Alan D. Neubert, Paul Szklennik, Vivienne Tedesco, James Thompson, David Truong, Qing Yang, Brian K. Hubbard, Michael H. Serrano-Wu
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.