title: Stereoselective synthesis of a novel 2-aza-7-oxabicyclo[3.3.0]octane as neurokinin-1 receptor antagonist.
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.
authors.affiliation: Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2394, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shishido
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Ito
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Morita
authors.forename: Masaya
authors.initials: M
authors.lastname: Ikunaka
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D004639:Emetics / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D009795:Octanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: C525806:2-aza-7-oxabicyclo(3.3.0)octane; D001372:Aza Compounds; D015220:Calcium Channels; D004639:Emetics; D064729:Neurokinin-1 Receptor Antagonists; D009795:Octanes; D018040:Receptors, Neurokinin-1; C026728:octane