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 E2 (PGE2) 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 PGE2. 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 fatal bleeding. The platelet EP3 receptor for PGE2, like the P2Y12 receptor, also inhibits cAMP synthesis. However, unlike ADP, facilitation of platelet aggregation via the PGE2/EP3 pathway is dependent on co-agonists that can mobilize Ca2+. We used a ligand-based design strategy to develop peri-substituted bicylic acylsulfonamides as potent and selective EP3 antagonists. We show that...