Nakajima, Katsumasa, Chatelain, Ricardo, Clairmont, Kevin, Commerford, Susan, Coppola, Gary, Daniels, Thomas, Forster, Cornelia, Gilmore, Thomas, Gong, Yongjin, Jain, Monish, Kanter, Aaron, Kwak, Young-Shin, Li, Jingzhou, Meyers, Charles, Neubert, Alan, Szklennik, Paul, Tedesco, Vivienne, Thompson, Jed, Truong, David, Yang, Qing, Hubbard, Brian and Serrano-Wu, Michael (2017) 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. Journal of Medicinal Chemistry, 60 (11). pp. 4657-4664. ISSN 15204804

Abstract

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.

Item Type:	Article
Date Deposited:	22 Jul 2017 00:45
Last Modified:	25 Jan 2019 00:45
URI:	https://oak.novartis.com/id/eprint/31336