Chiral tetrahydroquinoline derivatives as potent anti-hyperalgesic agents in animal models of sustained inflammation and chronic neuropathic pain.
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.
Di Fabio
Romano
R
GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy. rdf26781@gsk.com
Alvaro
Giuseppe
G
Bertani
Barbara
B
Donati
Daniele
D
Pizzi
Domenica Maria
DM
Gentile
Gabriella
G
Pentassuglia
Giorgio
G
Giacobbe
Simone
S
Spada
Simone
S
Ratti
Emiliangelo
E
Corsi
Mauro
M
Quartaroli
Mauro
M
Barnaby
Robert J
RJ
Vitulli
Giovanni
G
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
D006873:Hydroquinones; D005998:Glycine; C031927:hydroquinone