title: Discovery of GSK345931A: An EP(1) receptor antagonist with efficacy in preclinical models of inflammatory pain.
abstract: Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP(1) receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative 4 which displayed molecular weight of 414.9g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound 7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9g/mol). In addition, 7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.
authors.affiliation: Neurosciences 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: Christopher
authors.initials: C
authors.lastname: Budd
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Clayton
authors.forename: Gerard M P
authors.initials: GM
authors.lastname: Giblin
authors.forename: Paul
authors.initials: P
authors.lastname: Goldsmith
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hayhow
authors.forename: David N
authors.initials: DN
authors.lastname: Hurst
authors.forename: Alan
authors.initials: A
authors.lastname: Naylor
authors.forename: D
authors.initials: D
authors.lastname: Anthony Rawlings
authors.forename: Tiziana
authors.initials: T
authors.lastname: Scoccitti
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wilson
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Winchester
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D007249:Inflammation / Q000188:drug therapy*; D010146:Pain / Q000188:drug therapy*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013329:Structure-Activity Relationship
chemical_list: C538709:GSK345931A; C545636:Ptger1 protein, mouse; C545637:Ptger1 protein, rat; D011725:Pyridines; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype