title: Synthesis and structure-activity relationships of a series of (1H-pyrazol-4-yl)acetamide antagonists of the P2X7 receptor.
abstract: 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.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, CM19 5AW, United Kingdom. laura.j.chambers@gsk.com
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Chambers
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Stevens
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Moses
authors.forename: Anton D
authors.initials: AD
authors.lastname: Michel
authors.forename: Daryl S
authors.initials: DS
authors.lastname: Walter
authors.forename: David J
authors.initials: DJ
authors.lastname: Davies
authors.forename: David G
authors.initials: DG
authors.lastname: Livermore
authors.forename: Elena
authors.initials: E
authors.lastname: Fonfria
authors.forename: Emmanuel H
authors.initials: EH
authors.lastname: Demont
authors.forename: Mythily
authors.initials: M
authors.lastname: Vimal
authors.forename: Pam J
authors.initials: PJ
authors.lastname: Theobald
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Beswick
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gleave
authors.forename: Shilina A
authors.initials: SA
authors.lastname: Roman
authors.forename: Stefan
authors.initials: S
authors.lastname: Senger
mesh_terms: 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
chemical_list: 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