title: Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part II: Optimization of 4-(pyrrolidin-1-yl)benzonitrile derivatives.
abstract: We recently reported a class of novel tissue-selective androgen receptor modulators (SARMs), represented by a naphthalene derivative A. However, their pharmacokinetic (PK) profiles were poor due to low metabolic stability. To improve the PK profiles, we modified the hydroxypyrrolidine and benzonitrile substituents of 4-(pyrrolidin-1-yl)benzonitrile derivative B, which had a comparable potency as that of compound A. This optimization led us to further modifications, which improved metabolic stability while maintaining potent androgen agonistic activity. Among the synthesized compounds, (2S,3S)-2,3-dimethyl-3-hydroxylpyrrolidine derivative 1c exhibited a suitable PK profile and improved metabolic stability. Compound 1c demonstrated significant efficacy in levator ani muscle without increasing the weight of the prostate in an in vivo study. In addition, compound 1c showed agonistic activity in the CNS, which was detected using sexual behavior induction assay.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: mo.masayume@gmail.com.
authors.forename: Moriteru
authors.initials: M
authors.lastname: Asano
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takenori
authors.initials: T
authors.lastname: Hitaka
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Imada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Morimoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Shinohara
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Hara
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masuo
authors.initials: M
authors.lastname: Yamaoka
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Santou
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Imai
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Habuka
authors.affiliation: Structural Biology, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Yano
authors.affiliation: Structural Biology, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Wilson
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: atsushi.hasuoka@takeda.com.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hasuoka
mesh_terms: D045930:Anabolic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000728:Androgens / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D005058:Eunuchism / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: D045930:Anabolic Agents; D000728:Androgens; D009570:Nitriles; D011759:Pyrrolidines; D011944:Receptors, Androgen; C014356:benzonitrile; C032519:pyrrolidine
keywords: 4-(Pyrrolidin-1-yl)benzonitrile; Androgen receptor; Liver microsomal metabolic stability; Pharmacokinetics (PK); Selective androgen receptor modulators (SARMs)