Anti-androgenic effects of S-40542, a novel non-steroidal selective androgen receptor modulator (SARM) for the treatment of benign prostatic hyperplasia

Prostate. 2012 Oct 1;72(14):1580-7. doi: 10.1002/pros.22511. Epub 2012 Mar 16.


Background: Selective androgen receptor modulators (SARMs) would provide alternative therapeutic agent for androgen-related diseases. We identified a tetrahydroquinoline (THQ) derivative, 1-(8-nitro-3a, 4, 5, 9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl) ethane-1, 2-diol (S-40542) as a novel SARM antagonist.

Methods: Affinity for nuclear receptors of S-40542 was evaluated in receptor-binding studies. Androgen receptor (AR) transcriptional activity of S-40542 was investigated by luciferase reporter assay in DU145AR cells. Normal and benign prostatic hyperplasia (BPH) model rats were repeatedly treated with S-40542 and flutamide. The tissue weights of prostate and levator ani muscle as well as blood levels of testosterone and luteinizing hormone were measured.

Results: S-40542 bound to the AR with high affinity. S-40542 at relatively high concentrations increased the transcriptional activity. This agent also showed a concentration-dependent AR antagonistic action in the presence of 1 nM 5α-dihydrotestosterone. Repeated treatment with S-40542 and flutamide decreased dose-dependently the weights of the prostate to a similar extent. In contrast, the tissue weight-reducing effect by S-40542 treatment on the levator ani muscle was much weaker than that of flutamide. S-40542 had little effect on the blood level of testosterone and luteinizing hormone, whereas flutamide increased the level of both hormones. Furthermore, S-40542 decreased dose-dependently prostate weight of BPH rats.

Conclusions: The current results indicate that S-40542 possesses the prostate-selective SARM activity, suggestive of clinical benefit against benign prostate hyperplasia. THQ compounds may be useful for the research of mode of action of SARMs and for the development of safe SARM antagonists.

MeSH terms

  • Animals
  • Binding, Competitive
  • Cell Line
  • Humans
  • Inhibitory Concentration 50
  • Luteinizing Hormone / blood
  • Male
  • Nonsteroidal Anti-Androgens / pharmacology*
  • Organ Size / drug effects
  • Prostatic Hyperplasia / blood
  • Prostatic Hyperplasia / drug therapy*
  • Prostatic Hyperplasia / metabolism
  • Prostatic Hyperplasia / pathology
  • Quinolines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Androgen / metabolism
  • Regression Analysis
  • Testosterone / blood


  • AR protein, human
  • Nonsteroidal Anti-Androgens
  • Quinolines
  • Receptors, Androgen
  • Testosterone
  • Luteinizing Hormone