Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064

  • Bioorg Med Chem Lett. 2008 Aug 1;18(15):4339-43. doi: 10.1016/j.bmcl.2008.06.073.
Adwoa Akwabi-Ameyaw  1 ,  Jonathan Y Bass ,  Richard D Caldwell ,  Justin A Caravella ,  Lihong Chen ,  Katrina L Creech ,  David N Deaton ,  Stacey A Jones ,  Istvan Kaldor ,  Yaping Liu ,  Kevin P Madauss ,  Harry B Marr ,  Robert B McFadyen ,  Aaron B Miller ,  Frank Navas III ,  Derek J Parks ,  Paul K Spearing ,  Dan Todd ,  Shawn P Williams ,  G Bruce Wisely
Affiliations
  • 1. Department of Medicinal Chemistry, GlaxoSmithKline, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA.
PMID: 18621523 DOI: 10.1016/j.bmcl.2008.06.073
Abstract

Starting from the known FXR Agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR Agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.

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