2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2007 Jan 15;17(2):385-9. doi: 10.1016/j.bmcl.2006.10.041.
Gerard M P Giblin 1,  Rino A Bit,  Susan H Brown,  Hélène M Chaignot,  Anita Chowdhury,  Iain P Chessell,  Nicholas M Clayton,  Tanya Coleman,  Adrian Hall,  Beverley Hammond,  David N Hurst,  Anton D Michel,  Alan Naylor,  Riccardo Novelli,  Tiziana Scoccitti,  David Spalding,  Sac P Tang,  Alex W Wilson,  Rich Wilson
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry and DMPK, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. ged.m.giblin@gsk.com
PMID: 17084082 DOI: 10.1016/j.bmcl.2006.10.041
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.

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