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.

Discovery of glyantrypine‐family alkaloids as novel antiviral and antiphytopathogenic‐fungus agents

“…1,4-Oxazepane is a good pharmacophore that widely exists in drug molecules. [22][23][24][25] To increase the structural diversity, compounds 11a-11c and 13 containing 1,4-oxazepane were designed and synthesized on the basis of retaining the glyantrypine alkaloid quinazolinone structure (Fig. 3).…”

Design, synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors – Part 3

“…Biological evaluation of highly peripheral-selective noradrenaline reuptake inhibitors (NRIs) have been studied in our laboratory. 1,2 Peripheral-selective NRIs are assumed to have several advantages with respect to safety and efficacy over traditional central-acting NRIs as anti-SUI agents. 3 We previously reported 7-phenyl-6-substituted oxazepane derivatives as peripheral-selective NRIs.…”

“…3 We previously reported 7-phenyl-6-substituted oxazepane derivatives as peripheral-selective NRIs. 1,2 In these studies, our chemical modification focused on enhancing peripheral norepinephrine transporter (NET) selectivity and reducing the multidrug resistance protein 1 (MDR1) efflux ratio to mitigate drugdrug interaction (DDI) risks. P-glycoprotein (P-gp) is the major efflux transporter at the blood-brain barrier and is responsible for the efflux of a number of xenobiotic substances from the central nervous system.…”

“…The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc) to give 18b (148 mg, 100%) as a colorless oil 1. H NMR (300 MHz, CDCl 3 ) δ 1.51 (9H, s),7R)-tert-Butyl 7-(4-chloro-3-fluorophenyl)-6-((2-oxopiperidin-1-yl)methyl)-1,4-oxazepane-4-carboxylate (19b).…”