Stereoselective synthesis of a novel 2-aza-7-oxabicyclo[3.3.0]octane as neurokinin-1 receptor antagonist

Yuji Shishido; Fumitaka Ito; Hiromasa Morita; Masaya Ikunaka

doi:10.1016/j.bmcl.2007.10.010

Stereoselective synthesis of a novel 2-aza-7-oxabicyclo[3.3.0]octane as neurokinin-1 receptor antagonist

Bioorg Med Chem Lett. 2007 Dec 15;17(24):6887-90. doi: 10.1016/j.bmcl.2007.10.010. Epub 2007 Oct 5.

Authors

Yuji Shishido¹, Fumitaka Ito, Hiromasa Morita, Masaya Ikunaka

Affiliation

¹ Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2394, Japan.

PMID: 17967540
DOI: 10.1016/j.bmcl.2007.10.010

Abstract

A novel neurokinin-1 receptor antagonist, (+/-)-(1R( *),3S( *),4S( *),5S( *))-4-[(N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-3-phenyl-2-aza-7-oxabicyclo[3.3.0]octane (1), was synthesized stereoselectively using Padwa's intramolecular 1,3-dipolar cycloaddition methodology as the key step. Compound (+/-)-1 showed high affinity for the NK-1 receptors in human IM-9 cells with an IC(50) value of 0.22 nM. This new structural scaffold demonstrated significant in vivo antagonistic activity in the guinea pig ureter capsaicin-induced plasma extravasation model with an ED(50) value of 1-10mg/kg, po.

MeSH terms

Animals
Aza Compounds / chemical synthesis*
Aza Compounds / chemistry
Aza Compounds / pharmacology*
Calcium Channels / metabolism
Emetics / chemistry
Emetics / pharmacology
Humans
Inhibitory Concentration 50
Molecular Structure
Neurokinin-1 Receptor Antagonists*
Octanes / chemical synthesis*
Octanes / chemistry
Octanes / pharmacology*
Protein Binding
Receptors, Neurokinin-1 / metabolism
Stereoisomerism

Substances

2-aza-7-oxabicyclo(3.3.0)octane
Aza Compounds
Calcium Channels
Emetics
Neurokinin-1 Receptor Antagonists
Octanes
Receptors, Neurokinin-1
octane