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

Shuwen He, Zhong Lai, Qingmei Hong, Jackie Shang, Mikhail Reibarkh, Jeffrey T. Kuethe, Jian Liu, Deodial Guiadeen, Arto D. Krikorian, Timothy A. Cernak, Kevin D. Dykstra, Donald M. Sperbeck, Zhicai Wu, Yang Yu, Ginger X. Yang, Tianying Jian, Andreas Verras, Lisa M. Sonatore, Judyann Wiltsie, Christine C. ChungBeth A. Murphy, Judith N. Gorski, Jinqi Liu, Jianying Xiao, Michael Wolff, Sharon X. Tong, Maria Madeira, Bindhu V. Karanam, Dong Ming Shen, James M. Balkovec, Shirly Pinto, Ravi P. Nargund, Robert J. DeVita

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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.

Original languageEnglish
Pages (from-to)1182-1186
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number10
StatePublished - 15 May 2019
Externally publishedYes


  • Benzimidazole
  • DGAT1
  • Inhibitor
  • Isomerization
  • [3.1.0] bicyclohexane carboxylic acid


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