Novel nonsteroidal ligands with high binding affinity and potent functional activity for the androgen receptor

Eur J Med Chem. 2002 Aug;37(8):619-34. doi: 10.1016/s0223-5234(02)01335-1.


While nonsteroidal androgen receptor (AR) antagonists have been known for many years, and used in the clinic for the treatment of hormone dependent prostate cancer, very little is known about nonsteroidal AR agonists. We designed and synthesized a series of chiral bicalutamide analogs, which bear electron-withdrawing groups (either a cyano or a nitro group at the 4-position and a trifluoromethyl group at the 3-position) in the aromatic A ring, and different substituents at the para position in the aromatic B ring of the parent molecule. We also synthesized a series of racemic bicalutamide analogs, which have a trifluoromethyl group instead of a methyl group at the R(2) position. We examined AR binding affinities of our compounds in a competitive binding assay with a radiolabeled high affinity AR ligand, 3H-mibolerone, and also measured their abilities to stimulate AR-mediated transcriptional activation in a cotransfection assay. These studies demonstrated that (1) nonsteroidal ligands can be structurally modified from known nonsteroidal antiandrogens to generate ligands capable of activating AR-mediated transcriptional activation. (2) R-isomer analogs exhibit higher AR binding affinity and more potent functional activity than their corresponding S-isomers in all cases. (3) All sulphide analogs show higher AR binding affinity and more potent functional activity than their corresponding sulphone analogs, with the exception of ligand R-8. Those ligands which exhibit high AR binding affinity and potent functional activity for human AR may provide effective clinical uses for male fertility, male contraception, and hormone replacement therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androgens*
  • Anilides / chemical synthesis*
  • Anilides / pharmacology
  • Animals
  • Cell Line
  • Chlorocebus aethiops
  • Drug Design
  • Humans
  • Hydrocarbons, Aromatic / chemical synthesis
  • Hydrocarbons, Aromatic / pharmacology
  • Ligands
  • Nitriles
  • Radioligand Assay
  • Receptors, Androgen / genetics
  • Structure-Activity Relationship
  • Tosyl Compounds
  • Transcription, Genetic / drug effects
  • Transfection


  • Androgens
  • Anilides
  • Hydrocarbons, Aromatic
  • Ligands
  • Nitriles
  • Receptors, Androgen
  • Tosyl Compounds
  • bicalutamide