title: Discovery and structure-activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor.
abstract: 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.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.
authors.forename: Muna H
authors.initials: MH
authors.lastname: Abdi
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Beswick
authors.forename: Andy
authors.initials: A
authors.lastname: Billinton
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Chambers
authors.forename: Andrew
authors.initials: A
authors.lastname: Charlton
authors.forename: Sue D
authors.initials: SD
authors.lastname: Collins
authors.forename: Katharine L
authors.initials: KL
authors.lastname: Collis
authors.forename: David K
authors.initials: DK
authors.lastname: Dean
authors.forename: Elena
authors.initials: E
authors.lastname: Fonfria
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gleave
authors.forename: Clarisse L
authors.initials: CL
authors.lastname: Lejeune
authors.forename: David G
authors.initials: DG
authors.lastname: Livermore
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Medhurst
authors.forename: Anton D
authors.initials: AD
authors.lastname: Michel
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Moses
authors.forename: Lee
authors.initials: L
authors.lastname: Page
authors.forename: Sadhana
authors.initials: S
authors.lastname: Patel
authors.forename: Shilina A
authors.initials: SA
authors.lastname: Roman
authors.forename: Stefan
authors.initials: S
authors.lastname: Senger
authors.forename: Brian
authors.initials: B
authors.lastname: Slingsby
authors.forename: Jon G A
authors.initials: JG
authors.lastname: Steadman
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Stevens
authors.forename: Daryl S
authors.initials: DS
authors.lastname: Walter
mesh_terms: 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
chemical_list: D000577:Amides; D058919:Purinergic P2 Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D011761:Pyrrolidonecarboxylic Acid