title: Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part I.
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.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-85555, Japan. Electronic address: katsuji.aikawa@takeda.com.
authors: Katsuji
authors: K
authors: Aikawa
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-85555, Japan.
authors: Toshio
authors: T
authors: Miyawaki
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-85555, Japan.
authors: Takenori
authors: T
authors: Hitaka
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-85555, Japan.
authors: Yumi N
authors: YN
authors: Imai
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-85555, Japan.
authors: Takahito
authors: T
authors: Hara
authors: Pharmaceutical Production Division, Takeda Pharmaceutical Company Ltd, 17-85 Jusohommachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
authors: Junichi
authors: J
authors: Miyazaki
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-85555, Japan.
authors: Masuo
authors: M
authors: Yamaoka
authors: CMC Center, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-85555, Japan.
authors: Masami
authors: M
authors: Kusaka
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-85555, Japan.
authors: Naoyuki
authors: N
authors: Kanzaki
authors: Environment & Safety Department, Takeda Pharmaceutical Company Ltd, 17-85 Jusohommachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
authors: Akihiro
authors: A
authors: Tasaka
authors: Laboratories of Medicinal & Organic Chemistry Pharmaceutical Sciences, Himeji Dokkyo University, 7-2-1, Kamiohno, Himeji-shi, Hyogo 670-8524, Japan.
authors: Mitsuru
authors: M
authors: Shiraishi
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-85555, Japan.
authors: Satoshi
authors: S
authors: Yamamoto
mesh_terms: D045930:Anabolic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000728:Androgens / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002369:Castration; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009284:Naphthols / Q000138:chemical synthesis* / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012726:Sexual Behavior, Animal / Q000187:drug effects; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000494:pharmacology
chemical_list: D045930:Anabolic Agents; D000728:Androgens; D009284:Naphthols; D011759:Pyrrolidines; D011944:Receptors, Androgen; D013739:Testosterone
keywords: AR; Androgen receptor; Selective androgen receptor modulators (SARMs); Testosterone