Synthesis and pharmacological validation of a novel series of non-steroidal FXR agonists

  • Bioorg Med Chem Lett. 2010 Aug 15;20(16):4911-7. doi: 10.1016/j.bmcl.2010.06.084.
Ulrich Abel  1 ,  Thomas Schlüter ,  Andreas Schulz ,  Eva Hambruch ,  Christoph Steeneck ,  Martin Hornberger ,  Thomas Hoffmann ,  Sanja Perović-Ottstadt ,  Olaf Kinzel ,  Michael Burnet ,  Ulrich Deuschle ,  Claus Kremoser
Affiliations
  • 1. Phenex Pharmaceuticals AG, Waldhofer Strasse 104, 69123 Heidelberg, Germany.
PMID: 20638278 DOI: 10.1016/j.bmcl.2010.06.084
Abstract

To overcome the known liabilities of GW4064 a series of analogs were synthesized where the stilbene double bond is replaced by an oxymethylene or amino-methylene linker connecting a terminal benzoic acid with a substituted heteroaryl in the middle ring position. As a result we discovered compounds with increased potency in vitro that cause dose-dependent reduction of plasma triglycerides and Cholesterol in db/db mice down to 2 x 1 mg/kg/day upon oral administration.