Non-steroidal antiandrogens: synthesis and biological profile of high-affinity ligands for the androgen receptor

J Steroid Biochem Mol Biol. 1994 Jan;48(1):111-9. doi: 10.1016/0960-0760(94)90257-7.


New N-substituted arylthiohydantoin antiandrogens were synthesized. These compounds presented exceptionally high relative binding affinities (RBAs) for the rat androgen receptor (AR): up to 3 times that of testosterone (T) and 100 times the RBAs of non-steroidal antiandrogens such as flutamide, Casodex and Anandron. Furthermore, unlike available markers for AR, they were totally devoid of any binding to the other steroid receptors. RU 59063, the molecule with the highest RBA, was tritiated. When it was compared to [3H]T for the assay of rat, mouse, hamster and human AR, it gave rise to the same number of binding sites but its K alpha (6 x 10(9) M-1) for rat and human AR were, respectively 3 and 8 times higher than that of T. Moreover RU 59063, unlike T, was devoid of any specific binding to human plasma. In vivo, these compounds displayed antiandrogenic activity while being devoid of any agonistic effect. Thus, RU 56187, given orally in castrated male animals, prevented in a dose-dependent manner the effects of 3 mg/kg testosterone propionate (TP) on mouse renal ornithine decarboxylase (acute test) and of 0.5 mg/kg TP on rat prostate weight (chronic test). In these two models, its ED50 was 0.6 and 1 mg/kg, respectively. In the intact rat, when given alone, it inhibited dose-dependently the effect of endogenous androgens on the seminal vesicles (ED50 approximately 1 mg/kg) and prostate (ED50 approximately 3 mg/kg) weights. These results suggest that these new compounds may be useful as specific markers for the androgen receptor as well as for the treatment of androgen-dependent diseases or disorders such as prostate cancer, acne, hirsutism and male pattern baldness.

MeSH terms

  • Androgen Antagonists / chemical synthesis*
  • Androgen Antagonists / metabolism
  • Animals
  • Cell Line
  • Cricetinae
  • Genitalia, Male / anatomy & histology
  • Humans
  • Imidazoles / metabolism
  • Ligands
  • Male
  • Mice
  • Nitriles / metabolism
  • Organ Size
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Androgen / metabolism*
  • Sex Hormone-Binding Globulin / metabolism
  • Species Specificity
  • Structure-Activity Relationship
  • Testosterone / metabolism


  • Androgen Antagonists
  • Imidazoles
  • Ligands
  • Nitriles
  • Receptors, Androgen
  • Sex Hormone-Binding Globulin
  • RU 59063
  • Testosterone