Platelet adhesion and aggregation are pivotal events in arterial thrombosis thus making platelets the target of several important classes of antithrombotic agents. Platelets possess two P2Y receptors, P2Y1 and P2Y12, whose combined action is necessary for a full activation and aggregation response to stimulation by adenosine diphosphate (ADP).1 P2Y1 is responsible for the mobilization of ionized calcium from internal stores and mediates shape change. P2Y12 mediates a progressive and sustained aggregation not preceded by shape change. Modulation of P2 receptors in platelets may be of great importance in regulating platelet function, and, as a consequence, in controlling thromboyic diseases. P2Y12 is the target of ticlopidine and clopidogrel, two members of the family of thienopyridines, which block ADP receptor after a metabolic conversion in vivo to active metabolites that are thought to covalently modify the receptors. Recently, two ATP analogs, AR-C69931 MX and AR-C67085, were reported to be potent and selective P2Y12 receptor antagonists. They strongly inhibit ADP-induced activation in vitro without interfering with shape change or calcium mobilization.2,3 Based upon these results, we focused our attention to the development of a new class of potential P2Y12 antagonists structurally related to the reported antagonists, but extremely semplified.
Substituted 6-amino-thiouracils as new P2Y(12) receptor antagonists
CACCIARI, Barbara;
2007
Abstract
Platelet adhesion and aggregation are pivotal events in arterial thrombosis thus making platelets the target of several important classes of antithrombotic agents. Platelets possess two P2Y receptors, P2Y1 and P2Y12, whose combined action is necessary for a full activation and aggregation response to stimulation by adenosine diphosphate (ADP).1 P2Y1 is responsible for the mobilization of ionized calcium from internal stores and mediates shape change. P2Y12 mediates a progressive and sustained aggregation not preceded by shape change. Modulation of P2 receptors in platelets may be of great importance in regulating platelet function, and, as a consequence, in controlling thromboyic diseases. P2Y12 is the target of ticlopidine and clopidogrel, two members of the family of thienopyridines, which block ADP receptor after a metabolic conversion in vivo to active metabolites that are thought to covalently modify the receptors. Recently, two ATP analogs, AR-C69931 MX and AR-C67085, were reported to be potent and selective P2Y12 receptor antagonists. They strongly inhibit ADP-induced activation in vitro without interfering with shape change or calcium mobilization.2,3 Based upon these results, we focused our attention to the development of a new class of potential P2Y12 antagonists structurally related to the reported antagonists, but extremely semplified.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
