title: 1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists: Structure-activity relationships of 4- and 5-substituted benzoic acid derivatives.
abstract: This paper details the SAR of 1,5-biaryl pyrrole derivatives with substituents in the 2-, 4-, and 5-positions of the benzoic acid group as EP1 receptor antagonists. Substitution at the 2-position was poorly tolerated, whereas only fluorine was tolerated at the 4-position. In contrast, a range of substituents at the 5-position were discovered which enhanced the in vitro affinity and led to compounds with promising oral exposure. Three derivatives showed efficacy in a preclinical model of inflammatory pain when dosed orally to rats.
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
mesh_terms: D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D010146:Pain / Q000188:drug therapy / Q000209:etiology; 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: D001565:Benzoates; D011758:Pyrroles; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype