Novel substituted isoxazole FXR agonists with cyclopropyl, hydroxycyclobutyl and hydroxyazetidinyl linkers: Understanding and improving key determinants of pharmacological properties

Bioorg Med Chem Lett. 2016 Aug 1;26(15):3746-53. doi: 10.1016/j.bmcl.2016.05.070. Epub 2016 May 24.


Several isoxazole-containing series of FXR agonists have been published over the last 15years, subsequent to the prototypical amphiphilic 'hammerhead'-type structure that was originally laid out by GW4064, the first potent synthetic FXR agonist. A set of novel compounds where the hammerhead is connected to the terminal carboxylic acid-bearing aryl or heteroaryl moiety by either a cyclopropyl, a hydroxycyclobutyl or a hydroxyazetidinyl linker was synthesized in order to improve upon the ADME properties of such isoxazoles. The resulting compounds all demonstrated high potencies at the target receptor FXR but with considerable differences in their physicochemical and in vivo profiles. The structure-activity relationships for key chemical features that have a major impact on the in vivo pharmacology of this series are discussed.

Keywords: C57BL/6J mice; FXR agonist; Farnesoid X receptor; GW4064; High fat diet; NAFLD; NASH.

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Molecular Structure
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Structure-Activity Relationship


  • Isoxazoles
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor