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

F. Hoffmann-La Roche Ltd, Pharmaceutical Research, Grenzacherstrasse, CH-4070 Basel, Switzerland.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.65). 02/2011; 21(4):1134-40. 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.

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