P1P4-Dithio-P2P3-monochloromethylene diadenosine 5′5‴-P1P4-tetraphosphate: A novel antiplatelet agent

摘要

We have previously demonstrated in a series of searches for antithrombotic agents that diadenosine 5′,5‴-P¹,P⁴-tetraphosphate (AppppA) and its analogues are competitive inhibitors of ADP-induced platelet aggregation. Among various analogues, the P²,P³-monochloromethylene analog of AppppA (AppCHClppA) is superior to unmodified AppppA in its antiplatelet and antithrombotic effects. In this communication, we compare the antiplatelet potency of five newly synthesized agents with that of AppCHClppA. The five new agents include four diadenosine polyphosphate analogues [ApspCHClppsA (ps indicates a thiophosphate), dAppCHClppdA, dApspCHClppsdA, and AppCHClpCHClppA], and an adenosine tetraphosphate analogue (AppCHClpCHClp). When tested for their inhibitory effects on platelet aggregation by ADP, the most promising agent among them was ApspCHClppsA. Both molecular and functional integrity of this compound proved to be stable in blood at 37°C for at least 3 h. It also showed an excellent heat stability. This agent inhibits a number of aspects of ADP-induced platelet activation—e.g., release reaction, cytoplasmic calcium mobilization, thromboxane production, fibrinogen binding sites, and platelet factor 3 activity. Moreover, platelet aggregation induced by agonists other than ADP—e.g., arachidonic acid, collagen, and epinephrine—was inhibited partially by ApspCHClppsA. It is concluded that (i) ApspCHClppsA is a promising antiplatelet agent; (ii) it is resistant to blood phosphodiesterases and stable to heat treatment; (iii) platelet aggregation induced by collagen, epinephrine, or arachidonic acid is also inhibited in part by this agent; and (iv) specificity of the inhibitory effects is presented by unmodified adenosine moieties of the agent. Resistance to phosphodiesterases raises the possibility of oral administration.