Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part I. Issue 10 (15th May 2015)

• Record Type: Journal Article
• Authors: Aikawa, Katsuji; Miyawaki, Toshio; Hitaka, Takenori; Imai, Yumi N.; Hara, Takahito; Miyazaki, Junichi; Yamaoka, Masuo; Kusaka, Masami; Kanzaki, Naoyuki; Tasaka, Akihiro; Shiraishi, Mitsuru; Yamamoto, Satoshi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 10(2015)
• Page Start: 2568
• Page End: 2578
• Publication Date: 2015-05-15
• Subjects: Androgen receptor -- AR -- Selective androgen receptor modulators (SARMs) -- Testosterone; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.03.032
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 compoundA identified through high-throughput screening. Among the prepared compounds, 1-(4-cyano-1-naphthyl)-2, 3-disubstituted pyrrolidine derivatives17h, 17m, and17j 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.