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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

Nakajima, Katsumasa and Chatelain, Ricardo and Clairmont, Kevin and Commerford, Susan and Coppola, Gary and Daniels, Thomas and Forster, Cornelia and Gilmore, Thomas and Gong, Yongjin and Jain, Monish and Kanter, Aaron and Kwak, Young-Shin and Li, Jingzhou and Meyers, Charles and Neubert, Alan and Szklennik, Paul and Tedesco, Vivienne and Thompson, Jed and Truong, David and Yang, Qing and 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

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