The P2Y1 Receptor as a Target for New Antithrombotic Drugs: A Review of the P2Y1
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MRS-2179 is a selective P2Y1 receptor antagonist, a strong inhibitor of ADP-induced
platelet aggregation in vitro and ex vivo. By i.v. administration to mice MRS-2179 increases
resistance to thromboembolism induced by a mixture of collagen and epinephrine
or by a tissue factor. Likewise, it significantly increases the time to thrombus formation in a ferric chloride-induced model of localized arterial thrombosis. MRS-2179 also confers
resistance to localized venous thrombosis, which is dependent on thrombin generation and
in which platelets play a relatively minor role as compared to stasis or activation of coagulation.These data provide considerable encouragement for the development of new P2Y1
receptor antagonists. Nevertheless, the properties of MRS-2179 indicate that new compounds
should be optimized in order to increase the half-life of the molecule in vivo and
its selectivity and potency at the P2Y1 receptor. Further directions include the synthesis of molecules with modifications of the nucleotide structure which replace the fragile moiety by a stable bond and should lead to a non-hydrolysable structure. In conclusion, P2Y1 antagonists have been shown to be efficient antithrombotic agents. MRS-2179 is the first P2Y1 antagonist with antithrombotic action. Its effectiveness demonstrates that the P2Y1 receptor is a potentially promising target for drugs designed to treat thrombotic
syndromes., http://www.100md.com
platelet aggregation in vitro and ex vivo. By i.v. administration to mice MRS-2179 increases
resistance to thromboembolism induced by a mixture of collagen and epinephrine
or by a tissue factor. Likewise, it significantly increases the time to thrombus formation in a ferric chloride-induced model of localized arterial thrombosis. MRS-2179 also confers
resistance to localized venous thrombosis, which is dependent on thrombin generation and
in which platelets play a relatively minor role as compared to stasis or activation of coagulation.These data provide considerable encouragement for the development of new P2Y1
receptor antagonists. Nevertheless, the properties of MRS-2179 indicate that new compounds
should be optimized in order to increase the half-life of the molecule in vivo and
its selectivity and potency at the P2Y1 receptor. Further directions include the synthesis of molecules with modifications of the nucleotide structure which replace the fragile moiety by a stable bond and should lead to a non-hydrolysable structure. In conclusion, P2Y1 antagonists have been shown to be efficient antithrombotic agents. MRS-2179 is the first P2Y1 antagonist with antithrombotic action. Its effectiveness demonstrates that the P2Y1 receptor is a potentially promising target for drugs designed to treat thrombotic
syndromes., http://www.100md.com