Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor. Issue 15 (1st August 2015)

• Record Type: Journal Article
• Authors: Fujimori, Ikuo; Yukawa, Tomoya; Kamei, Taku; Nakada, Yoshihisa; Sakauchi, Nobuki; Yamada, Masami; Ohba, Yusuke; Takiguchi, Maiko; Kuno, Masako; Kamo, Izumi; Nakagawa, Hideyuki; Hamada, Teruki; Igari, Tomoko; Okuda, Teruaki; Yamamoto, Satoshi; Tsukamoto, Tetsuya; Ishichi, Yuji; Ueno, Hiroyuki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 15(2015)
• Page Start: 5000
• Page End: 5014
• Publication Date: 2015-08-01
• Subjects: SUI stress urinary incontinence -- DAT dopamine transporter -- SERT serotonin transporter -- NET norepinephrine transporter -- hERG human ether-a-go-go-related gene K+ channel -- CNS central nervous system -- Boc tert-butoxycarbonyl; Peripheral-selective noradrenaline reuptake inhibitor -- Stress urinary incontinence -- 7-Aryl-1, 4-oxazepane derivatives; 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.2015.05.017
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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. (6 S, 7 R )-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 -{[(6 S, 7 R )-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.