Discovery of potent and selective adamantane-based small-molecule P2X(7) receptor antagonists/interleukin-1beta inhibitors.
A novel series of antagonists of the human P2X7 receptor is described. Modification of substituents enabled identification of compounds selective for the rat P2X7 receptor and provides useful pharmacological tools for evaluation of the role of P2X7 in disease.
Furber
Mark
M
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leics, U.K. mark1.furber@astrazeneca.com
Alcaraz
Lilian
L
Bent
Janice E
JE
Beyerbach
Armin
A
Bowers
Keith
K
Braddock
Martin
M
Caffrey
Moya V
MV
Cladingboel
David
D
Collington
John
J
Donald
David K
DK
Fagura
Malbinder
M
Ince
Frank
F
Kinchin
Elizabeth C
EC
Laurent
Celine
C
Lawson
Mandy
M
Luker
Timothy J
TJ
Mortimore
Michael M P
MM
Pimm
Austen D
AD
Riley
Robert J
RJ
Roberts
Nicola
N
Robertson
Mark
M
Theaker
Jill
J
Thorne
Philip V
PV
Weaver
Richard
R
Webborn
Peter
P
Willis
Paul
P
D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation; D009000:Monocytes / Q000378:metabolism; D011485:Protein Binding; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D058486:Receptors, Purinergic P2X7; D013329:Structure-Activity Relationship
D001549:Benzamides; D001798:Blood Proteins; D053583:Interleukin-1beta; C546468:P2RX7 protein, human; C546470:P2rx7 protein, rat; D058919:Purinergic P2 Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D000218:Adamantane