title: The discovery of 6-[2-(5-chloro-2-{[(2,4-difluorophenyl)methyl]oxy}phenyl)-1-cyclopenten-1-yl]-2-pyridinecarboxylic acid, GW848687X, a potent and selective prostaglandin EP1 receptor antagonist for the treatment of inflammatory pain.
abstract: The discovery of a series of selective EP1 receptor antagonists based on a 1,2-diarylcyclopentene template is described. After defining the structural requirements for EP1 potency and selectivity, heterocyclic rings were incorporated to reduce logD and improve in vitro pharmacokinetic properties. The 2,6-substituted pyridines and pyridazines gave an appropriate balance of potency, in vivo pharmacokinetic properties and a low potential for inhibiting a range of CYP450 enzymes. From this series, GW848687X was shown to have an excellent profile in models of inflammatory pain and was selected as a development candidate.
authors.affiliation: Department of Medicinal Chemistry and DMPK, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. ged.m.giblin@gsk.com
authors.forename: Gerard M P
authors.initials: GM
authors.lastname: Giblin
authors.forename: Rino A
authors.initials: RA
authors.lastname: Bit
authors.forename: Susan H
authors.initials: SH
authors.lastname: Brown
authors.forename: Hélène M
authors.initials: HM
authors.lastname: Chaignot
authors.forename: Anita
authors.initials: A
authors.lastname: Chowdhury
authors.forename: Iain P
authors.initials: IP
authors.lastname: Chessell
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Clayton
authors.forename: Tanya
authors.initials: T
authors.lastname: Coleman
authors.forename: Adrian
authors.initials: A
authors.lastname: Hall
authors.forename: Beverley
authors.initials: B
authors.lastname: Hammond
authors.forename: David N
authors.initials: DN
authors.lastname: Hurst
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: Tiziana
authors.initials: T
authors.lastname: Scoccitti
authors.forename: David
authors.initials: D
authors.lastname: Spalding
authors.forename: Sac P
authors.initials: SP
authors.lastname: Tang
authors.forename: Alex W
authors.initials: AW
authors.lastname: Wilson
authors.forename: Rich
authors.initials: R
authors.lastname: Wilson
mesh_terms: D000527:Alprostadil / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005620:Freund's Adjuvant; D006207:Half-Life; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*
chemical_list: C518619:6-(2-(5-chloro-2-(((2,4-difluorophenyl)methyl)oxy)phenyl)-1-cyclopenten-1-yl)-2-pyridinecarboxylic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003517:Cyclopentanes; D011725:Pyridines; D018078:Receptors, Prostaglandin E; D005620:Freund's Adjuvant; D003577:Cytochrome P-450 Enzyme System; D000527:Alprostadil