Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

  • Bioorg Med Chem Lett. 2009 Jun 1;19(11):2969-73. doi: 10.1016/j.bmcl.2009.04.047.
Jonathan Y Bass  1 ,  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 ,  Derek J Parks ,  Dan Todd ,  Shawn P Williams ,  G Bruce Wisely
Affiliations
  • 1. Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
PMID: 19410460 DOI: 10.1016/j.bmcl.2009.04.047
Abstract

Starting from the known FXR Agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.