Hemostasis is essential body defense mechanism for prevention of bleeding from damaged blood vessels. Platelets are essential for hemostasis and blood clotting.
Abnormal hemostasis can result in formation of blood clots as a consequence of platelet aggregation. Incidence of blood clots in arteries can increase of the risk of stroke and heart attack1. Adenosine-5′-diphosphate (ADP) is an endogenous mediator of platelet activation and aggregation through activation of Gq-coupled P2Y1 receptors and Gi-coupled P2Y12 receptors on the surface of platelets2. Blocking of P2Y12 receptors is essential for prevention of platelet aggregation. There are well-known P2Y12 antagonists such as thienopyridine derivatives (ticlopidine, clopidogrel and prasugrel) and ticagrelor which used for treatment of stroke and myocardial infarction (MI) in patients with acute coronary syndrome (ACS)3. Despite their proven antiplatelet activity, thienopyridines are prodrugs and need to metabolic bioactivation, so some of them have slow onset e.g. clopidogrel4.
Active metabolites of clopidogrel and prasugrel bind irreversibly to P2Y12 receptor that may result in prolonged bleeding in some patients. The use of competitive antagonists such as cangrelor is more suitable for those patients. However, cangrelor is a nucleotide analogue and so has poor bioavailability and short plasma half life time after oral administration. Recently, a non-nucleotide analogue ticagrelor has been reported to act as orally active competitive P2Y12 antagonist2. However, there are several side effects reported during ticagrelor treatment such as dyspnea (shortness of breath), ventricular pauses and hyperuricemia5. In addition, ticagrelor is CYP3A4 substrate and inhibitor that can result in drug-drug interaction when coadministered with CYP3A4 inhibitors e.
g. ketoconazole and clarithromycin6. As such, there is a need for development of novel competitive P2Y12 antagonists with high efficacy and without associated side effects.