Antagonists of the EP3 Receptor for Prostaglandin E2 Are Novel Antiplatelet Agents That Do Not Prolong Bleeding

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 Ca2+ and through the P2Y12 receptor can inhibit cAMP production, causing platelet activation and aggregation. Clopidogrel (Plavix), a selective P2Y12 antagonist, prevents platelets from clotting but thereby increases the risk of severe or fata bleeding. The platelet EP3 receptor for PGE(2), like the P2Y12 receptor, also inhibits cAMP synthesis. However, unlike ADP, facilitation of platelet aggregation via the PGE(2)/EP3 pathway is dependent on co-agonists that can mobilize Ca2+. We used a ligand-based design strategy to develop peri-substituted bicylic acylsulfon-amides as potent and selective EP3 antagonists. We show that DG-041, a selective EP3 antagonist, inhibits PGE(2) facilitation of platelet aggregation in vitro and ex vivo. PGE(2) can resensitize platelets to agonists even when the P2Y12 receptor has been blocked by clopidogrel, and this can be inhibited by DG-041. Unlike clopidogrel, DG-041 is co-administrered with clopidogrel. This indicates that EP3 antagonists potentially have a superior safety profile compared to P2Y12 antagonists and represent a novel class of antiplatelet agents.