New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors
Department of Pediatrics, Division of Hematology Oncology; Center for Platelet Function Studies
Medicinal and Pharmaceutical Chemistry | Medicinal-Pharmaceutical Chemistry
Currently approved platelet adenosine diphosphate (ADP) receptor antagonists target only the platelet P2Y12 receptor. Moreover, especially in patients with acute coronary syndromes, there is a strong need for rapidly acting and reversible antiplatelet agents in order to minimize the risk of thrombotic events and bleeding complications. In this study, a series of new P(1),P(4)-di(adenosine-5') tetraphosphate (Ap4A) derivatives with modifications in the base and in the tetraphosphate chain were synthesized and evaluated with respect to their effects on platelet aggregation and function of the platelet P2Y1, P2Y12, and P2X1 receptors. The resulting structure-activity relationships were used to design Ap4A analogs which inhibit human platelet aggregation by simultaneously antagonizing both P2Y1 and P2Y12 platelet receptors. Unlike Ap4A, the analogs do not activate platelet P2X1 receptors. Furthermore, the new compounds exhibit fast onset and offset of action and are significantly more stable than Ap4A to degradation in plasma, thus presenting a new promising class of antiplatelet agents.
Acute coronary syndromes, Adenosine diphosphate, Antiplatelet therapy, Antithrombotics, Bis-nucleoside polyphosphates, Cardiovascular disease, Dinucleoside polyphosphates, Inhibitors, P2X1, P2Y(1), P2Y(12), Platelets
DOI of Published Version
Eur J Med Chem. 2016 Jan 1;107:204-18. doi: 10.1016/j.ejmech.2015.10.055. Epub 2015 Nov 9. Link to article on publisher's site
European journal of medicinal chemistry
Yanachkov, Ivan B.; Chang, Hung; Yanachkova, Milka; Dix, Edward J.; Berny-Lang, Michelle A.; Gremmel, Thomas; Michelson, Alan D.; Wright, George E.; and Frelinger, Andrew L. III, "New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors" (2016). Pediatric Publications and Presentations. 70.