Title of article :
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
Author/Authors :
Gerard M.P. Giblin، نويسنده , , Rino A. Bit، نويسنده , , Susan H. Brown، نويسنده , , Helene M. Chaignot، نويسنده , , Anita Chowdhury، نويسنده , , Iain P. Chessell، نويسنده , , Nicholas M. Clayton، نويسنده , , Tanya Coleman، نويسنده , , Adrian Hall، نويسنده , , Beverley Hammond، نويسنده , , David N. Hurst، نويسنده , , Anton D. Michel، نويسنده , , Alan Naylor، نويسنده , , Riccardo Novelli، نويسنده , , Tiziana Scoccitti، نويسنده , , David Spalding، نويسنده , , Sac P. Tang، نويسنده , , Alex W. Wilson، نويسنده , , Rich Wilson، نويسنده ,
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 log D 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.
