Format

Send to

Choose Destination
Bioorg Med Chem. 2015 May 15;23(10):2568-78. doi: 10.1016/j.bmc.2015.03.032. Epub 2015 Mar 19.

Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part I.

Author information

1
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-85555, Japan. Electronic address: katsuji.aikawa@takeda.com.
2
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-85555, Japan.
3
Pharmaceutical Production Division, Takeda Pharmaceutical Company Ltd, 17-85 Jusohommachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
4
CMC Center, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-85555, Japan.
5
Environment & Safety Department, Takeda Pharmaceutical Company Ltd, 17-85 Jusohommachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
6
Laboratories of Medicinal & Organic Chemistry Pharmaceutical Sciences, Himeji Dokkyo University, 7-2-1, Kamiohno, Himeji-shi, Hyogo 670-8524, Japan.

Abstract

To develop effective drugs for hypogonadism, sarcopenia, and cachexia, we designed, synthesized, and evaluated selective androgen receptor modulators (SARMs) that exhibit not only anabolic effects on organs such as muscles and the central nervous system (CNS) but also neutral or antagonistic effects on the prostate. Based on the information obtained from a docking model with androgen receptor (AR), we modified a hit compound A identified through high-throughput screening. Among the prepared compounds, 1-(4-cyano-1-naphthyl)-2,3-disubstituted pyrrolidine derivatives 17h, 17m, and 17j had highly potent AR agonistic activities in vitro and good tissue selectivity in vivo. These derivatives increased the weight of the levator ani muscle without influencing the prostate and seminal vesicle. In addition, these compounds induced sexual behavior in castrated rats, indicating that the compounds could also act as agonists on the CNS.

KEYWORDS:

AR; Androgen receptor; Selective androgen receptor modulators (SARMs); Testosterone

PMID:
25862209
DOI:
10.1016/j.bmc.2015.03.032
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center