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.
1. 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. 2. 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. 4. 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). 4. GW627368X appears to bind to human prostanoid TP receptors but not the TP receptors of other species. In human washed platelets, GW627368X (10 microM) produced 100% inhibition of U-46619 (EC100)-induced aggregation (approximate pA2 approximately 7.0). However, in rings of rabbit and piglet saphenous vein and of guinea-pig aorta GW627368X (10 microM) did not displace U-46619 E/[A] curves indicating an affinity of < 5.0 for rabbit and guinea-pig prostanoid TP receptors. 5. In functional assays GW627368X is devoid of both agonism and antagonist affinity for prostanoid CRTH2, 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 < 5.0. 6. In competition radioligand bioassays, GW627368X had affinity for human prostanoid EP4 and TP receptors (pKi = 7.0 +/- 0.2 (n = 10) and 6.8 (n = 2), respectively). Affinity for all other human prostanoid receptors was < 5.3. 7. GW627368X will be a valuable tool to explore the role of the prostanoid EP4 receptor in many physiological and pathological settings.
Wilson
Richard J
RJ
Screening and Compound Profiling, Discovery Research, GlaxoSmithKline R & D, New Frontiers Science Park, Third Avenue, Harlow CM19 5AW. rich.j.wilson@gsk.com
Giblin
Gerard M P
GM
Roomans
Susan
S
Rhodes
Sharron A
SA
Cartwright
Kerri-Ann
KA
Shield
Vanessa J
VJ
Brown
Jason
J
Wise
Alan
A
Chowdhury
Jannatara
J
Pritchard
Sara
S
Coote
Jim
J
Noel
Lloyd S
LS
Kenakin
Terry
T
Burns-Kurtis
Cynthia L
CL
Morrison
Valerie
V
Gray
David W
DW
Giles
Heather
H
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001555:Benzene Derivatives / Q000494:pharmacology*; D002460:Cell Line; D015232:Dinoprostone / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D054833:Isoindoles; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D011869:Radioligand Assay; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D017482:Receptors, Thromboxane / Q000378:metabolism; D012501:Saphenous Vein / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013552:Swine
D001555:Benzene Derivatives; D007211:Indoles; D054833:Isoindoles; C515270:N-(2-(4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo(f)isoindol-2-yl)phenyl)acetyl)benzene sulphonamide; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D015232:Dinoprostone