title: 1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists. Structure-activity relationships of 6-substituted and 5,6-disubstituted benzoic acid derivatives.
abstract: Herein we describe the SAR of 1,5-biaryl pyrrole derivatives, with substituents in the 6-position of the benzoic acid moiety, as EP(1) receptor antagonists. Substitution at this position was well tolerated and led to the identification of several analogues with high affinity for the EP(1) receptor that displayed good efficacy in the established FCA model of inflammatory pain. Furthermore, several analogues were prepared which combined substitution at the 5- and 6-positions as well as derivatives with an aromatic ring fused to the 5- and 6-positions.
authors.affiliation: Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. adrian.2.hall@gsk.com
authors.forename: Adrian
authors.initials: A
authors.lastname: Hall
authors.forename: Susan H
authors.initials: SH
authors.lastname: Brown
authors.forename: Iain P
authors.initials: IP
authors.lastname: Chessell
authors.forename: Anita
authors.initials: A
authors.lastname: Chowdhury
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Clayton
authors.forename: Tanya
authors.initials: T
authors.lastname: Coleman
authors.forename: Gerard M P
authors.initials: GM
authors.lastname: Giblin
authors.forename: Beverley
authors.initials: B
authors.lastname: Hammond
authors.forename: Mark P
authors.initials: MP
authors.lastname: Healy
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Johnson
authors.forename: Ann
authors.initials: A
authors.lastname: Metcalf
authors.forename: Anton D
authors.initials: AD
authors.lastname: Michel
authors.forename: Alan
authors.initials: A
authors.lastname: Naylor
authors.forename: Riccardo
authors.initials: R
authors.lastname: Novelli
authors.forename: David J
authors.initials: DJ
authors.lastname: Spalding
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sweeting
authors.forename: Lisa
authors.initials: L
authors.lastname: Winyard
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D001565:Benzoates; D007202:Indicators and Reagents; C545635:PTGER1 protein, human; D011758:Pyrroles; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D003577:Cytochrome P-450 Enzyme System