We have previously demonstrated in a series of searches for antithrombotic agents that diadenosine 5,5ٟ-P 1 , P 4 -tetraphosphate (AppppA) and its analogues are competitive inhibitors of ADP-induced platelet aggregation. Among various analogues, the P 2 , P When tested for their inhibitory effects on platelet aggregation by ADP, the most promising agent among them was Ap s pCHClpp s A. 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 Ap s pCHClpp s A. It is concluded that (i) Ap s pCHClpp s A 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.

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