Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties

ArticleinBioorganic & medicinal chemistry letters 21(4):1134-40 · February 2011with8 Reads
Impact Factor: 2.42 · DOI: 10.1016/j.bmcl.2010.12.123 · Source: PubMed

    Abstract

    Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice. (c) 2011 Elsevier Ltd. All rights reserved.