This Phase I application proposes to characterize three newly- developed chemical analogues of diadenosine-5',5'''-P1P4 tetraphosphate (AP4A) for their antiplatelet potency. These new AP4A analogues will be characterized with respect to (1) inhibition of ADP-induced platelet aggregation, (2) effect on platelet release reactions and platelet factor 3 activity, (3) effects on the regulatory factors in platelet activation, (4) effect on aggregating agents other than ADP, (5) time-dependent effect on ADP-induced platelet aggregation in whole blood systems, (6) stability of the agent in whole blood, (7) distribution of the agent in different components of blood, and (8) test for aggregatability of platelets previously exposed to the agent. A clear demonstration of superior in vitro antiplatelet activity in one or all of these analogues would ultimately lead to in-vivo Phase II testing. Accordingly, the proposed Phase I studies, if successful, have a clear connection to Phase II studies.
