title: Structure-activity relationships of 1,5-biaryl pyrroles as EP1 receptor antagonists.
abstract: The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2mg/kg.
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: Stephen
authors.initials: S
authors.lastname: Atkinson
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: Robert J
authors.initials: RJ
authors.lastname: Gleave
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: 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: Sac P
authors.initials: SP
authors.lastname: Tang
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000494:pharmacology*; D001682:Biological Availability; D003510:Cyclohexanes / Q000737:chemistry; D003517:Cyclopentanes / Q000737:chemistry; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008024:Ligands; D010146:Pain / Q000188:drug therapy / Q000473:pathology; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D001565:Benzoates; D003510:Cyclohexanes; D003517:Cyclopentanes; D008024:Ligands; D011758:Pyrroles; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype