title: Synthesis and biological activity of a series of tetrasubstituted-imidazoles as P2X(7) antagonists.
abstract: 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.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. robert.j.gleave@gsk.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gleave
authors.forename: Daryl S
authors.initials: DS
authors.lastname: Walter
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Beswick
authors.forename: Elena
authors.initials: E
authors.lastname: Fonfria
authors.forename: Anton D
authors.initials: AD
authors.lastname: Michel
authors.forename: Shilina A
authors.initials: SA
authors.lastname: Roman
authors.forename: Sac-Pham
authors.initials: SP
authors.lastname: Tang
mesh_terms: 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
chemical_list: 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