A new drug agent, 747 agent, has been discovered as a potent antithrombotic. It exhibits a long-lasting and rapid onset of action, and has a strong inhibition of platelet aggregation. It is currently under clinical evaluation for the treatment of thrombotic diseases. In vitro studies suggest that 747 agent inhibits platelet aggregation by selectively interfering with the Gi-linked P2T receptor on the membrane surface of rat platelets.
747 agent is orally active and has a concentration-dependent activity against in vitro platelet aggregation. The inhibitory action of 747 agent on platelet aggregation is mediated by an irreversible modification of the Gi-linked P2T receptor on its membrane surface. In addition to the direct inhibition of platelet aggregation, 747 agent also neutralized ADP-induced decreases in cyclic AMP levels. Its effects on platelet shape were measured at four hours after the oral administration of the compound.
In vivo inhibition of ADP-induced platelet aggregation was evaluated in a rat model of arterial thrombosis. In this study, 747 agent was administered in rats orally at doses of 0.3 and 3 mg kg-1. After four hours of dosing, a significant and sustained inhibition of platelet aggregation was observed. This was not reversed by washing the platelets. However, it did not affect platelet shape changes induced by the P2Y1 receptor. The ED50 value of 747 agent was 0.68 mg kg-1. Moreover, the duration of the inhibition of platelet aggregation was comparable to the life span of circulating platelets in the rat.
747 agent showed an inhibitory effect against ADP-induced platelet aggregation in the presence of clopidogrel. Similarly, 747 agent inhibited the formation of thrombus in the rat model of arterio-venous shunt thrombosis. Its antithrombotic properties were also evaluated in a rat bleeding-time assay. Compared with clopidogrel, 747 agent was more potent. It also had an antihaemostatic effect in the rat bleeding-time assay. In this study, 747 agent exerted an effect similar to ticlopidine.
In vivo activity of 747 agent is associated with the formation of a new active metabolite. This metabolite interferes with the Gi-linked P2T receptor, producing an inhibition of ADP-induced platelet aggregates. In addition, a pharmacokinetic evaluation of the active metabolite suggested that it was a potent and selective inhibitor of Gi-linked P2T receptors.
The in vitro activities of 747 agent are also similar to those of ticlopidine. It inhibited in vitro platelet aggregation in concentration-related and dose-dependent fashion. Moreover, 747 agent showed an inhibitory effect on in vitro platelet aggregation induced by the prostaglandin E1 receptor. It also produced a significant inhibition of the aggregation induced by thrombin. In addition, 747 agent also inhibited the ex vivo platelet aggregation induced with thrombin and prostaglandin E1 (PGE1). This activity was further supported by the inhibitory activity of the metabolite on ADP-induced platelet aggregation, collagen-induced aggregation, and PGE1-induced aggregation in rat platelets.
Despite its inhibitory effects, 747 agent did not exhibit fibrinolytic or anticoagulant actions. Its in vitro inhibitory activity is likely to be due to an interaction with the Gi-linked P2T receptor. As such, it is not easy to determine whether it can act as an effective antiplatelet agent in clinical trials.
