Design, synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors – Part 3. Issue 16 (15th August 2016)

• Record Type: Journal Article
• Authors: Yukawa, Tomoya; Nakada, Yoshihisa; Sakauchi, Nobuki; Kamei, Taku; Yamada, Masami; Ohba, Yusuke; Fujimori, Ikuo; Ueno, Hiroyuki; Takiguchi, Maiko; Kuno, Masako; Kamo, Izumi; Nakagawa, Hideyuki; Fujioka, Yasushi; Igari, Tomoko; Ishichi, Yuji; Tsukamoto, Tetsuya
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 16(2016)
• Page Start: 3716
• Page End: 3726
• Publication Date: 2016-08-15
• Subjects: SUI Stress urinary incontinence -- DAT dopamine transporter -- SERT serotonin transporter -- NET norepinephrine transporter -- MDR1 multidrug resistance protein 1 -- P-gp P-glycoprotein; Peripheral-selective noradrenaline reuptake inhibitor -- 7-Aryl-1, 4-oxazepane derivatives -- Stress urinary incontinence -- MDR1 efflux ratio -- Intramolecular hydrogen bond; 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.2016.06.014
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Peripheral-selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Here, we describe our medicinal chemistry approach to discover a novel series of highly potent, peripheral-selective, and orally available noradrenaline reuptake inhibitors with a low multidrug resistance protein 1 (MDR1) efflux ratio by cyclization of an amide moiety and introduction of an acidic group. We observed that the MDR1 efflux ratio was correlated with the p K a value of the acidic moiety. The resulting compound9 exhibited favorable PK profiles, probably because of the effect of intramolecular hydrogen bond, which was supported by a its single-crystal structure. The compound9, 1-{[(6 S, 7 R )-7-(4-chloro-3-fluorophenyl)-1, 4-oxazepan-6-yl]methyl}-2-oxo-1, 2-dihydropyridine-3-carboxylic acid hydrochloride, which exhibited peripheral NET-selective inhibition at tested doses in rats by oral administration, increased urethral resistance in a dose-dependent manner.