title: Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor.
abstract: Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This report describes the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats. (6S,7R)-1,4-Oxazepane derivative 7 exhibited noradrenaline transporter inhibition with high selectivity against inhibitions of serotonin and dopamine transporters. A replacement of hydroxyl with acetamide group contributed to enhancement of peripheral selectivity by increasing molecular polarity. Compound 12, N-{[(6S,7R)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl}acetamide 0.5 fumarate, which showed effectively no brain penetration in rats, increased urethral resistance in a dose-dependent manner and exhibited a maximal effect on par with esreboxetine. These results demonstrate that the urethral resistance-increasing effects of NRI in rats are mainly caused by the inhibition of noradrenaline transporters in the peripheral sites.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Fujimori
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: tomoya.yukawa@takeda.com.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yukawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Kamei
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nakada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Nobuki
authors.initials: N
authors.lastname: Sakauchi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 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, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohba
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Takiguchi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Kuno
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Kamo
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Teruki
authors.initials: T
authors.lastname: Hamada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Igari
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Teruaki
authors.initials: T
authors.lastname: Okuda
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishichi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ueno
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D005260:Female; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D008968:Molecular Conformation; D009025:Morpholines / Q000627:therapeutic use; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014550:Urinary Incontinence, Stress / Q000188:drug therapy
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D006571:Heterocyclic Compounds; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; C541385:esreboxetine
keywords: 7-Aryl-1,4-oxazepane derivatives; Peripheral-selective noradrenaline reuptake inhibitor; Stress urinary incontinence