The platelet P2Y(1)
ADP receptor is an attractive target for new
antiplatelet drugs. However, because of the lack of strong and stable antagonists, only a few studies have suggested that pharmacological inhibition of the P2Y(1) receptor could efficiently inhibit experimental
thrombosis in vivo. Our aim was to determine whether the newly described potent and selective P2Y(1) receptor antagonist
MRS2500 [2-iodo-N(6)-methyl-(N)-methanocarba-2'-
deoxyadenosine-3',5'-bisphosphate] could inhibit platelet function ex vivo and experimental
thrombosis in mice in vivo.
MRS2500 was injected intravenously into mice, and its effect on ex vivo platelet aggregation and in several models of
thrombosis in vivo was determined.
MRS2500 displayed high potency and stable and selective P2Y(1) receptor inhibition ex vivo. Although
MRS2500 injection resulted in only moderate prolongation of the bleeding time, it provided strong protection in systemic
thromboembolism induced by infusion of a mixture of
collagen and
adrenaline.
MRS2500 also potently inhibited localized arterial
thrombosis in a model of
laser-induced vessel wall injury with two degrees of severity. Moreover, combination of
MRS2500 with
clopidogrel, the irreversible inhibitor of the platelet P2Y(12) receptor for
ADP, led to increased antithrombotic efficacy compared with each alone. These results add further evidence for a role of the P2Y(1) receptor in
thrombosis and validate the concept that targeting the P2Y(1) receptor could be a relevant alternative or
complement to current antiplatelet strategies.