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 P ₂Y₁₂ receptor can inhibit cAMP production, causing platelet activation and aggregation. Clopidogrel (Plavix), a selective P ₂Y₁₂ antagonist, prevents platelets from clotting but thereby increases the risk of severe or fatal bleeding. The platelet EP ₃ 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 acylsulfon- amides as potent and selective EP₃ antagonists. We show that DG-041, a selective EP ₃ antagonist, inhibits PGE₂ facilitation of platelet aggregation in vitro and ex vivo. PGE₂ can resensitize platelets to agonist even when the P₂Y₁₂ 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 P₂Y₁₂ antagonists and represent a novel class of antiplatelet agents.