Synthesis and structure-activity relationships of a series of (1H-pyrazol-4-yl)acetamide antagonists of the P2X7 receptor.
High-throughput screening identified compound 1 as a potent P2X(7) receptor antagonist suitable for lead optimisation. Structure-activity relationships (SAR) of a series of (1H-pyrazol-4-yl)acetamides were investigated and compound 32 was identified as a potent P2X(7) antagonist with enhanced potency and favourable physicochemical and pharmacokinetic properties.
Chambers
Laura J
LJ
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, CM19 5AW, United Kingdom. laura.j.chambers@gsk.com
Stevens
Alexander J
AJ
Moses
Andrew P
AP
Michel
Anton D
AD
Walter
Daryl S
DS
Davies
David J
DJ
Livermore
David G
DG
Fonfria
Elena
E
Demont
Emmanuel H
EH
Vimal
Mythily
M
Theobald
Pam J
PJ
Beswick
Paul J
PJ
Gleave
Robert J
RJ
Roman
Shilina A
SA
Senger
Stefan
S
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D057166:High-Throughput Screening Assays; D006801:Humans; D007275:Injections, Intravenous; D058919:Purinergic P2 Receptor Antagonists; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D013329:Structure-Activity Relationship
D000081:Acetamides; D000890:Anti-Infective Agents; C546468:P2RX7 protein, human; D058919:Purinergic P2 Receptor Antagonists; D011720:Pyrazoles; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7