Synthesis and biological activity of a series of tetrasubstituted-imidazoles as P2X(7) antagonists.
A series of analogues of the pyrazole lead 1 were synthesized in which the heterocyclic core was replaced with an imidazole. A number of potent antagonists were identified and structure-activity relationships (SAR) were investigated both with respect to activity at the P2X(7) receptor and in vitro metabolic stability. Compound 10 was identified as a potent P2X(7) antagonist with reduced in vitro metabolism and high solubility.
Gleave
Robert J
RJ
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. robert.j.gleave@gsk.com
Walter
Daryl S
DS
Beswick
Paul J
PJ
Fonfria
Elena
E
Michel
Anton D
AD
Roman
Shilina A
SA
Tang
Sac-Pham
SP
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D011720:Pyrazoles / Q000737:chemistry; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; C546468:P2RX7 protein, human; D058919:Purinergic P2 Receptor Antagonists; D011720:Pyrazoles; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; C031280:pyrazole