title: Chiral tetrahydroquinoline derivatives as potent anti-hyperalgesic agents in animal models of sustained inflammation and chronic neuropathic pain.
abstract: Chiral tetrahydroquinoline derivatives have been prepared by an asymmetric Mannich-type condensation reaction using commercially available vinyloxyethylsilane and a N-arylimino R-(+)-t-butyl lactate ester, in the presence of a catalytic amount of metal triflates as Lewis acids. This synthetic approach gave rise to the target aldehyde intermediate in moderate facial diastereoselectivity and in high chemical yield. This efficient route enabled to scale up the synthesis of an orally bioavailable glycine antagonist showing outstanding in vivo anti-hyperalgesic activity in different animal models of sustained inflammation and chronic neuropathic pain.
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy. rdf26781@gsk.com
authors.forename: Romano
authors.initials: R
authors.lastname: Di Fabio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Alvaro
authors.forename: Barbara
authors.initials: B
authors.lastname: Bertani
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Domenica Maria
authors.initials: DM
authors.lastname: Pizzi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gentile
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pentassuglia
authors.forename: Simone
authors.initials: S
authors.lastname: Giacobbe
authors.forename: Simone
authors.initials: S
authors.lastname: Spada
authors.forename: Emiliangelo
authors.initials: E
authors.lastname: Ratti
authors.forename: Mauro
authors.initials: M
authors.lastname: Corsi
authors.forename: Mauro
authors.initials: M
authors.lastname: Quartaroli
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Barnaby
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vitulli
mesh_terms: D000818:Animals; D001682:Biological Availability; D004195:Disease Models, Animal; D005998:Glycine / Q000037:antagonists & inhibitors*; D006873:Hydroquinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy; D010146:Pain / Q000188:drug therapy; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D006873:Hydroquinones; D005998:Glycine; C031927:hydroquinone