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.

Products