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Background  Diadenosine tetraphosphate (Ap 4 A), a constituent of platelet dense granules, and its P 1 ,P 4 -dithio and/or P 2 ,P 3 -chloromethylene analogs, inhibit adenosine diphosphate (ADP)-induced platelet aggregation. We recently reported that these compounds antagonize both platelet ADP receptors, P2Y 1  and P2Y 12 . The most active of those analogs, diadenosine 5′,5″″-P 1 ,P 4 -dithio-P 2 ,P 3 -chloromethylenetetraphosphate, (compound  1 ), exists as a mixture of 4 stereoisomers.    Objective  To separate the stereoisomers of compound  1  and determine their effects on platelet aggregation, platelet P2Y 1  and P2Y 12  receptor antagonism, and their metabolism in human plasma.    Methods  We separated the 4 diastereomers of compound  1  by preparative reversed-phase chromatography, and studied their effect on ADP-induced platelet aggregation, P2Y 1 -mediated changes in cytosolic Ca 2+ , P2Y 12 -mediated changes in VASP phosphorylation, and metabolism in human plasma.    Results  The inhibition of ADP-induced human platelet aggregation and human platelet P2Y 12  receptor, and stability in human plasma strongly depended on the stereo-configuration of the chiral P 1 - and P 4 -phosphorothioate groups, the S P S P  diastereomer being the most potent inhibitor and completely resistant to degradation in plasma, and the R P R P  diastereomer being the least potent inhibitor and with the lowest plasma stability. The inhibitory activity of S P R P  diastereomers depended on the configuration of the pseudo-asymmetric carbon of the P 2 ,P 3 -chloromethylene group, one of the configurations being significantly more active than the other. Their plasma stability did not differ significantly, being intermediate to that of the S P S P  and the R P R P  diastereomers.    Conclusions  The presently-described stereoisomers have utility for structural, mechanistic, and drug development studies of dual antagonists of platelet P2Y 1  and P2Y 12  receptors.

plos one

Antiplatelet Activity, P2Y1 and P2Y12 Inhibition, and Metabolism in Plasma of Stereoisomers of Diadenosine 5′,5′″-P1,P4-dithio-P2,P3-chloromethylenetetraphosphate