Design, synthesis, and biological evaluation of nonsteroidal cycloalkane[d]isoxazole-containing androgen receptor modulators

J Med Chem. 2012 Jul 26;55(14):6316-27. doi: 10.1021/jm300233k. Epub 2012 Jul 11.


We report here the design, preparation, and systematic evaluation of a novel cycloalkane[d]isoxazole pharmacophoric fragment-containing androgen receptor (AR) modulators. Cycloalkane[d]isoxazoles form new core structures that interact with the hydrophobic region of the AR ligand-binding domain. To systematize and rationalize the structure-activity relationship of the new fragment, we used molecular modeling to design a molecular library containing over 40 cycloalkane[d]isoxazole derivatives. The most potent compound, 4-(3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-3-yl)-2-(trifluoromethyl)benzonitrile (6a), exhibits antiandrogenic activity significantly greater than that of the most widely used antiandrogenic prostate cancer drugs bicalutamide (1) and hydroxyflutamide (2) in reporter gene assays measuring the transcriptional activity of AR (decreasing approximately 90% of the total AR activity) and in competitive AR ligand-binding assays (showing over four times higher potency to inhibit radioligand binding in comparison to bicalutamide). Notably, 6a maintains its antiandrogenic activity with AR mutants W741L and T877A commonly observed and activated by bicalutamide and hydroxyflutamide, respectively, in prostate cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chemistry Techniques, Synthetic
  • Chlorocebus aethiops
  • Cycloparaffins / chemistry*
  • Drug Design*
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Models, Molecular
  • Nonsteroidal Anti-Androgens / chemical synthesis*
  • Nonsteroidal Anti-Androgens / chemistry
  • Nonsteroidal Anti-Androgens / pharmacology*
  • Protein Conformation
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / metabolism*
  • Structure-Activity Relationship


  • Cycloparaffins
  • Isoxazoles
  • Nonsteroidal Anti-Androgens
  • Receptors, Androgen