Benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety

Autor:	Dong-Ming Shen, Michael Wolff, Shirly Pinto, Deodial Guiadeen, Bindhu V. Karanam, James M. Balkovec, Arto D. Krikorian, Shuwen He, Maria Madeira, Donald M. Sperbeck, Andreas Verras, Judyann Wiltsie, Jian Liu, Jackie Shang, Tim Cernak, Beth Ann Murphy, Qingmei Hong, Christine C. Chung, Ravi P. Nargund, Kevin D. Dykstra, Judith N. Gorski, Robert J. DeVita, Sharon Tong, Tianying Jian, Lisa M. Sonatore, Jeffrey T. Kuethe, Jianying Xiao, Jinqi Liu, Zhong Lai, Zhicai Wu, Mikhail Reibarkh, Ginger X. Yang, Yang Yu
Rok vydání:	2019
Předmět:	Benzimidazole Cyclohexane Stereochemistry Carboxylic acid Clinical Biochemistry Carboxylic Acids Pharmaceutical Science 01 natural sciences Biochemistry Mass Spectrometry Inhibitory Concentration 50 Mice chemistry.chemical_compound Isomerism In vivo Drug Discovery Animals Humans Moiety Diacylglycerol O-Acyltransferase Enzyme Inhibitors Molecular Biology Chromatography High Pressure Liquid Active metabolite chemistry.chemical_classification Cyclohexanones 010405 organic chemistry Chemistry Organic Chemistry In vitro Rats 0104 chemical sciences 010404 medicinal & biomolecular chemistry Hepatocytes Molecular Medicine Benzimidazoles Isomerization
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 29:1182-1186
ISSN:	0960-894X
DOI:	10.1016/j.bmcl.2019.03.025
Popis:	Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety. Our results show that single isomer 3A maintains in vitro and in vivo inhibition against DGAT1. In contrast to previous lead compounds, 3A does not undergo isomerization during in vitro hepatocyte incubation study or in vivo mouse study.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6d804bc7e0890d2b1abe6ee34b194779 https://doi.org/10.1016/j.bmcl.2019.03.025 Zobrazit plný text záznamu Full Text from ScienceDirect