Structure-activity relationships and in vivo activity of (1H-pyrazol-4-yl)acetamide antagonists of the P2X(7) receptor.
Structure-activity relationships (SAR) of analogues of lead compound 1 were investigated and compound 16 was selected for further study in animal models of pain. Compound 16 was shown to be a potent antihyperalgesic agent in both the rat acute complete Freund's adjuvant (CFA) model of inflammatory pain [Iadarola, M. J.; Douglass, J.; Civelli, O.; Naranjo, J. R. rain Res.1988, 455, 205] and the knee joint model of chronic inflammatory pain [Wilson, A. W.; Medhurst, S. J.; Dixon, C. I.; Bontoft, N. C.; Winyard, L. A.; Brackenborough, K. T.; De Alba, J.; Clarke, C. J.; Gunthorpe, M. J.; Hicks, G. A.; Bountra, C.; McQueen, D. S.; Chessell, I. P. Eur. J. Pain2006, 10, 537].
Beswick
Paul J
PJ
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK.
Billinton
Andy
A
Chambers
Laura J
LJ
Dean
David K
DK
Fonfria
Elena
E
Gleave
Robert J
RJ
Medhurst
Stephen J
SJ
Michel
Anton D
AD
Moses
Andrew P
AP
Patel
Sadhana
S
Roman
Shilina A
SA
Roomans
Sue
S
Senger
Stefan
S
Stevens
Alexander J
AJ
Walter
Daryl S
DS
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D010146:Pain / Q000188:drug therapy; D058920:Purinergic P2X Receptor Antagonists; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D013329:Structure-Activity Relationship
D000081:Acetamides; D058920:Purinergic P2X Receptor Antagonists; D011720:Pyrazoles; D058486:Receptors, Purinergic P2X7