title: Antagonists of the EP3 receptor for prostaglandin E2 are novel antiplatelet agents that do not prolong bleeding.
abstract: Myocardial infarction and stroke are caused by blood clots forming over a ruptured or denuded atherosclerotic plaque (atherothrombosis). Production of prostaglandin E(2) (PGE(2)) by an inflamed plaque exacerbates atherothrombosis and may limit the effectiveness of current therapeutics. Platelets express multiple G-protein coupled receptors, including receptors for ADP and PGE(2). ADP can mobilize Ca(2+) and through the P(2)Y(12) receptor can inhibit cAMP production, causing platelet activation and aggregation. Clopidogrel (Plavix), a selective P(2)Y(12) antagonist, prevents platelets from clotting but thereby increases the risk of severe or fatal bleeding. The platelet EP(3) receptor for PGE(2), like the P(2)Y(12) receptor, also inhibits cAMP synthesis. However, unlike ADP, facilitation of platelet aggregation via the PGE(2)/EP(3) pathway is dependent on co-agonists that can mobilize Ca(2+). We used a ligand-based design strategy to develop peri-substituted bicylic acylsulfonamides as potent and selective EP(3) antagonists. We show that DG-041, a selective EP(3) antagonist, inhibits PGE(2) facilitation of platelet aggregation in vitro and ex vivo. PGE(2) can resensitize platelets to agonist even when the P(2)Y(12) receptor has been blocked by clopidogrel, and this can be inhibited by DG-041. Unlike clopidogrel, DG-041 does not affect bleeding time in rats, nor is bleeding time further increased when DG-041 is co-administered with clopidogrel. This indicates that EP(3) antagonists potentially have a superior safety profile compared to P(2)Y(12) antagonists and represent a novel class of antiplatelet agents.
authors.affiliation: deCODE Chemistry, Woodridge, Illinois 60517, USA.
authors.forename: Jasbir
authors.initials: J
authors.lastname: Singh
authors.forename: Wayne
authors.initials: W
authors.lastname: Zeller
authors.forename: Nian
authors.initials: N
authors.lastname: Zhou
authors.forename: Georgeta
authors.initials: G
authors.lastname: Hategen
authors.forename: Rama
authors.initials: R
authors.lastname: Mishra
authors.forename: Alex
authors.initials: A
authors.lastname: Polozov
authors.forename: Peng
authors.initials: P
authors.lastname: Yu
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Onua
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Zembower
authors.forename: Alex
authors.initials: A
authors.lastname: Kiselyov
authors.forename: José L
authors.initials: JL
authors.lastname: Ramírez
authors.forename: Gudmundur
authors.initials: G
authors.lastname: Sigthorsson
authors.forename: Jon Mar
authors.initials: JM
authors.lastname: Bjornsson
authors.forename: Margret
authors.initials: M
authors.lastname: Thorsteinsdottir
authors.forename: Thorkell
authors.initials: T
authors.lastname: Andrésson
authors.forename: Maria
authors.initials: M
authors.lastname: Bjarnadottir
authors.forename: Olafur
authors.initials: O
authors.lastname: Magnusson
authors.forename: Jean-Etienne
authors.initials: JE
authors.lastname: Fabre
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Mark E
authors.initials: ME
authors.lastname: Gurney
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D000077144:Clopidogrel; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006470:Hemorrhage / Q000517:prevention & control; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058925:Receptors, Purinergic P2Y12; D013450:Sulfones / Q000494:pharmacology*; D013927:Thrombosis / Q000188:drug therapy / Q000378:metabolism; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C531572:3-(1-((2,4-dichlorophenyl)methyl)-5-fluoro-3-methyl-1H-indol-7-yl)-N-((4,5-dichloro-2-thienyl)sulfonyl)-2-propenamide; D000178:Acrylamides; C548576:P2RY12 protein, human; C545647:PTGER3 protein, human; D010975:Platelet Aggregation Inhibitors; D011448:Prostaglandin Antagonists; D058919:Purinergic P2 Receptor Antagonists; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058925:Receptors, Purinergic P2Y12; D013450:Sulfones; D000077144:Clopidogrel; D015232:Dinoprostone; D013988:Ticlopidine