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

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.
Olaf Kinzel 1,  Christoph Steeneck 2,  Thomas Schlüter 2,  Andreas Schulz 2,  Christian Gege 2,  Ulrike Hahn 3,  Eva Hambruch 2,  Martin Hornberger 2,  Adriana Spalwisz 2,  Katharina Frick 2,  Sanja Perović-Ottstadt 2,  Ulrich Deuschle 2,  Michael Burnet 3,  Claus Kremoser 2
Affiliations

Affiliations

  • 1 Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany. Electronic address: olaf.kinzel@phenex-pharma.com.
  • 2 Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany.
  • 3 Synovo GmbH, Paul-Ehrlich Str. 15, 72076 Tübingen, Germany.
PMID: 27268696 DOI: 10.1016/j.bmcl.2016.05.070
Abstract

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.

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