Get access

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

Authors

  • Hiroaki Nejishima,

    Corresponding author
    1. Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Fujieda, Shizuoka, Japan
    2. Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (GCOE) Program, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka, Japan
    • Kaken Pharmaceutical Co., Ltd., 301 Gensuke, Fujieda, Shizuoka 426-8646, Japan.
    Search for more papers by this author
  • Noriko Yamamoto,

    1. Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Fujieda, Shizuoka, Japan
    Search for more papers by this author
  • Mika Suzuki,

    1. Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Fujieda, Shizuoka, Japan
    Search for more papers by this author
  • Kazuyuki Furuya,

    1. Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Fujieda, Shizuoka, Japan
    Search for more papers by this author
  • Naoya Nagata,

    1. Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Fujieda, Shizuoka, Japan
    Search for more papers by this author
  • Shizuo Yamada

    1. Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (GCOE) Program, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka, Japan
    Search for more papers by this author

Abstract

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. Prostate 72:1580–1587, 2012. © 2012 Wiley Periodicals, Inc.

Ancillary