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: Ikuo Fujimori, Tomoya Yukawa, Taku Kamei, Yoshihisa Nakada, Nobuki Sakauchi, Masami Yamada, Yusuke Ohba, Maiko Takiguchi, Masako Kuno, Izumi Kamo, Hideyuki Nakagawa, Teruki Hamada, Tomoko Igari, Teruaki Okuda, Satoshi Yamamoto, Tetsuya Tsukamoto, Yuji Ishichi, Hiroyuki Ueno
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 15 Pg. 5000-5014 (Aug 01 2015) ISSN: 1464-3391 [Electronic] England
• PMID: 26051602 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Dopamine Plasma Membrane Transport Proteins
• Heterocyclic Compounds
• Morpholines
• Norepinephrine Plasma Membrane Transport Proteins
• Serotonin Plasma Membrane Transport Proteins
• Serotonin and Noradrenaline Reuptake Inhibitors
• esreboxetine

Topics

• Animals
• Cerebral Cortex (metabolism)
• Dopamine Plasma Membrane Transport Proteins (chemistry, metabolism)
• Drug Design
• Female
• Heterocyclic Compounds (chemical synthesis, chemistry, therapeutic use)
• Humans
• Molecular Conformation
• Morpholines (therapeutic use)
• Norepinephrine Plasma Membrane Transport Proteins (chemistry, metabolism)
• Rats
• Rats, Sprague-Dawley
• Serotonin Plasma Membrane Transport Proteins (chemistry, metabolism)
• Serotonin and Noradrenaline Reuptake Inhibitors (chemical synthesis, chemistry, therapeutic use)
• Stereoisomerism
• Structure-Activity Relationship
• Urinary Incontinence, Stress (drug therapy)