Discovery of a potent and selective DGAT1 inhibitor with a piperidinyl-oxy-cyclohexanecarboxylic acid moiety

Shuwen He, Qingmei Hong, Zhong Lai, David X. Yang, Pauline C. Ting, Jeffrey T. Kuethe, Timothy A. Cernak, Kevin D. Dykstra, Donald M. Sperbeck, Zhicai Wu, Yang Yu, Ginger X. Yang, Tianying Jian, Jian Liu, Deodial Guiadeen, Arto D. Krikorian, Lisa M. Sonatore, Judyann Wiltsie, Jinqi Liu, Judith N. GorskiChristine C. Chung, Jack T. Gibson, Jeanmarie Lisnock, 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

18 Scopus citations


We report the discovery of a novel series of DGAT1 inhibitors in the benzimidazole class with a piperdinyl-oxy-cyclohexanecarboxylic acid moiety. This novel series possesses significantly improved selectivity against the A2A receptor, no ACAT1 off-target activity at 10 μM, and higher aqueous solubility and free fraction in plasma as compared to the previously reported pyridyl-oxy-cyclohexanecarboxylic acid series. In particular, 5B was shown to possess an excellent selectivity profile by screening it against a panel of more than 100 biological targets. Compound 5B significantly reduces lipid excursion in LTT in mouse and rat, demonstrates DGAT1 mediated reduction of food intake and body weight in mice, is negative in a 3-strain Ames test, and appears to distribute preferentially in the liver and the intestine in mice. We believe this lead series possesses significant potential to identify optimized compounds for clinical development.

Original languageEnglish
Pages (from-to)1082-1087
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number10
StatePublished - 9 Oct 2014
Externally publishedYes


  • A receptor
  • ACAT1
  • Ames test
  • DGAT1
  • benzimidazole
  • cyclohexanecarboxylic acid
  • epimerization
  • inhibitor
  • lipid tolerance test
  • metabolite
  • skin


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