jm7b00173_si_001.csv (0.63 kB)
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
dataset
posted on 2017-05-12, 00:00 authored 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-WuModification
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.
