Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor

被引：7

作者：

Fujimori, Ikuo ^{[1
]}

Yukawa, Tomoya ^{[1
]}

Kamei, Taku ^{[1
]}

Nakada, Yoshihisa ^{[1
]}

Sakauchi, Nobuki ^{[1
]}

Yamada, Masami ^{[1
]}

Ohba, Yusuke ^{[1
]}

Takiguchi, Maiko ^{[1
]}

Kuno, Masako ^{[1
]}

Kamo, Izumi ^{[1
]}

Nakagawa, Hideyuki ^{[1
]}

Hamada, Teruki ^{[1
]}

Igari, Tomoko ^{[1
]}

Okuda, Teruaki ^{[1
]}

Yamamoto, Satoshi ^{[1
]}

Tsukamoto, Tetsuya ^{[1
]}

Ishichi, Yuji ^{[1
]}

Ueno, Hiroyuki ^{[1
]}

机构：

[1] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Fujisawa, Kanagawa 2518555, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 15期

关键词：

Peripheral-selective noradrenaline reuptake inhibitor; Stress urinary incontinence; 7-Aryl-1,4-oxazepane derivatives; URINARY-INCONTINENCE; RISK; PREVALENCE; URETHRA;

D O I：

10.1016/j.bmc.2015.05.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：5000 / 5014

页数：15

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