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.
ASJC Scopus subject areas
- Molecular Medicine