GW627368X ((N‐{2‐[4‐(4,9‐diethoxy‐1‐oxo‐1,3‐dihydro‐2H‐benzo[f]isoindol‐2‐yl)phenyl]acetyl} benzene sulphonamide): a novel, potent and selective prostanoid EP4 receptor antagonist

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Abstract
N‐{2‐[4‐(4,9‐diethoxy‐1‐oxo‐1,3‐dihydro‐2H‐benzo[f]isoindol‐2‐yl)phenyl]acetyl}benzene sulphonamide (GW627368X) is a novel, potent and selective competitive antagonist of prostanoid EP4 receptors with additional human TP receptor affinity. At recombinant human prostanoid EP4 receptors expressed in HEK293 cells, GW627368X produced parallel rightward shifts of PGE2 concentration–effect (E/[A]) curves resulting in an affinity (pKb) estimate of 7.9±0.4 and a Schild slpoe not significantly different from unity. The affinity was independent of the agonist used. In rings of phenylephrine precontracted piglet saphenous vein, GW627368X (30–300 nM) produced parallel rightward displacement of PGE2 E/[A] curves (pKb=9.2±0.2; slope=1). GW627368X appears to bind to human prostanoid TP receptors but not the TP receptors of other species. In human washed platelets, GW627368X (10 μM) produced 100% inhibition of U‐46619 (EC100)‐induced aggregation (approximate pA2 ∼7.0). However, in rings of rabbit and piglet saphenous vein and of guinea‐pig aorta GW627368X (10 μM) did not displace U‐46619 E/[A] curves indicating an affinity of 2, EP2, EP3, IP and FP receptors. At prostanoid EP1 receptors, GW627368X was an antagonist with a pA2 of 6.0, and at prostanoid IP receptors the compound increased the maximum effect of iloprost by 55%. At rabbit prostanoid EP2 receptors the pA2 of GW627368X was 4 and TP receptors (pKi=7.0±0.2 (n=10) and 6.8 (n=2), respectively). Affinity for all other human prostanoid receptors was 4 receptor in many physiological and pathological settings. British Journal of Pharmacology (2006) 148, 326–339. doi:10.1038/sj.bjp.0706726