Hemostasis stroke and heart attack1. Adenosine-5′-diphosphate (ADP) is an

 
        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.