Discovery and structure-activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor.
A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.
Abdi
Muna H
MH
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.
Beswick
Paul J
PJ
Billinton
Andy
A
Chambers
Laura J
LJ
Charlton
Andrew
A
Collins
Sue D
SD
Collis
Katharine L
KL
Dean
David K
DK
Fonfria
Elena
E
Gleave
Robert J
RJ
Lejeune
Clarisse L
CL
Livermore
David G
DG
Medhurst
Stephen J
SJ
Michel
Anton D
AD
Moses
Andrew P
AP
Page
Lee
L
Patel
Sadhana
S
Roman
Shilina A
SA
Senger
Stefan
S
Slingsby
Brian
B
Steadman
Jon G A
JG
Stevens
Alexander J
AJ
Walter
Daryl S
DS
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D008958:Models, Molecular; D058919:Purinergic P2 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry*; D058486:Receptors, Purinergic P2X7 / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000577:Amides; D058919:Purinergic P2 Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D011761:Pyrrolidonecarboxylic Acid