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

• Published in: British journal of pharmacology 2009-01, Vol.148 (3), p.326-339
• Main Authors: Wilson, Richard J, Giblin, Gerard M P, Roomans, Susan, Rhodes, Sharron A, Cartwright, Kerri‐Ann, Shield, Vanessa J, Brown, Jason, Wise, Alan, Chowdhury, Jannatara, Pritchard, Sara, Coote, Jim, Noel, Lloyd S, Kenakin, Terry, Burns‐Kurtis, Cynthia L, Morrison, Valerie, Gray, David W, Giles, Heather
• Format: Article
• Language: English
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0706726

N ‐{2‐[4‐(4,9‐diethoxy‐1‐oxo‐1,3‐dihydro‐2 H ‐benzo[ f ]isoindol‐2‐yl)phenyl]acetyl}benzene sulphonamide (GW627368X) is a novel, potent and selective competitive antagonist of prostanoid EP 4 receptors with additional human TP receptor affinity. At recombinant human prostanoid EP 4 receptors expressed in HEK293 cells, GW627368X produced parallel rightward shifts of PGE 2 concentration–effect ( E /[A]) curves resulting in an affinity (p K b ) 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 n M ) produced parallel rightward displacement of PGE 2 E /[A] curves (p K b =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  μ M ) produced 100% inhibition of U‐46619 (EC 100 )‐induced aggregation (approximate p A 2 ∼7.0). However, in rings of rabbit and piglet saphenous vein and of guinea‐pig aorta GW627368X (10  μ M ) did not displace U‐46619 E /[A] curves indicating an affinity of