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FXR agonist activity of conformationally constrained analogs of GW 4064
Authors:Adwoa Akwabi-Ameyaw  Jonathan Y Bass  Richard D Caldwell  Justin A Caravella  Lihong Chen  Katrina L Creech  David N Deaton  Kevin P Madauss  Harry B Marr  Robert B McFadyen  Aaron B Miller  Frank Navas  Derek J Parks  Paul K Spearing  Dan Todd  Shawn P Williams  G Bruce Wisely
Institution:1. Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA;2. Molecular Discovery Research, Computational and Structural Chemistry Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA;3. Department of Metabolic Diseases, GlaxoSmithKline, Research Triangle Park, NC 27709, USA;4. Molecular Discovery Research, Screening & Compound Profiling, GlaxoSmithKline, Research Triangle Park, NC 27709, USA;5. Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, NC 27709, USA;6. Molecular Discovery Research, Biological Reagents and Assay Development, GlaxoSmithKline, Research Triangle Park, NC 27709, USA;7. Department of Pharmaceutical Development, Physical Properties and Developability, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
Abstract:Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.
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