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

摘要

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