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.

Gerard M P Giblin, 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

文献索引：Bioorg. Med. Chem. Lett. 17(2) , 385-9, (2007)

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摘要

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.