Novel substituted isoxazole FXR agonists with cyclopropyl, hydroxycyclobutyl and hydroxyazetidinyl linkers: Understanding and improving key determinants of pharmacological properties.
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.
Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany. Electronic address: olaf.kinzel@phenex-pharma.com.
Olaf
O
Kinzel
Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany.
Christoph
C
Steeneck
Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany.
Thomas
T
Schlüter
Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany.
Andreas
A
Schulz
Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany.
Christian
C
Gege
Synovo GmbH, Paul-Ehrlich Str. 15, 72076 Tübingen, Germany.
Ulrike
U
Hahn
Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany.
Eva
E
Hambruch
Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany.
Martin
M
Hornberger
Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany.
Adriana
A
Spalwisz
Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany.
Katharina
K
Frick
Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany.
Sanja
S
Perović-Ottstadt
Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany.
Ulrich
U
Deuschle
Synovo GmbH, Paul-Ehrlich Str. 15, 72076 Tübingen, Germany.
Michael
M
Burnet
Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany.
Claus
C
Kremoser
D004305:Dose-Response Relationship, Drug; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013329:Structure-Activity Relationship; D000099150:Receptor, Farnesoid X-Activated
D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated
C57BL/6J mice; FXR agonist; Farnesoid X receptor; GW4064; High fat diet; NAFLD; NASH