Potent DGAT1 Inhibitors in the Benzimidazole Class with a Pyridyl-oxy-cyclohexanecarboxylic Acid Moiety

• DOI: 10.1021/ml400168h
• Publication Date: 2013-06-06T20:11:11Z
• Authors: Shuwen He; Qingmei Hong; Zhong Lai; Zhicai Wu; Yang Yu; David W. Kim; Pauline C. Ting; Jeffrey T. Kuethe; Ginger X. Yang; Tianying Jian; Jian Liu; Deodial Guiadeen; Arto D. Krikorian; Donald M. Sperbeck; Lisa M. Sonatore; Judyann Wiltsie; Christine C. Chung; Jack T. Gibson; JeanMarie Lisnock; Beth A. Murphy; Judith N. Gorski; Jinqi Liu; Dunlu Chen; Xiaoli Chen; Michael Wolff; Sharon X. Tong; Maria Madeira; Bindhu V. Karanam; Dong-Ming Shen; James M. Balkovec; Shirly Pinto; Ravi P. Nargund; Robert J. DeVita
• Keywords: Moiety; Benzimidazole; Cyclohexanecarboxylic acid

We report the design and synthesis of a series novel DGAT1 inhibitors in benzimidazole class with pyridyl-oxy-cyclohexanecarboxylic acid moiety. In particular, compound 11A is potent inhibitor excellent selectivity against ACAT1. Compound significantly reduces triglyceride excursion lipid tolerance tests (LTT) both mice dogs at low plasma exposure. An vivo study des-fluoro analogue 10A indicates that this compounds appears to distribute intestine preferentially over plasma. The propensity target could be advantageous reducing potential side effects since lower circulating levels drug are required for efficacy. However, preclinical species, undergoes cis/trans epimerization vivo, which complicate further development due presence an active metabolite.