Antagonists of the platelet P-2T receptor: A novel approach to antithrombotic therapy

The platelet P-2T receptor plays a major role in platelet aggregation, and its antagonists are predicted to have significant therapeutic potential as antithrombotic agents. We have explored analogues of adenosine triphosphate (ATP), which is a weak, nonselective but competitive P-2T receptor antagon ist. Modification of the polyphosphate side chain to prevent breakdown to t he agonist adenosine diphosphate (ADP) and substitution of the adenine moie ty to enhance affinity and selectivity for the P-2T receptor led to the ide ntification of 10e (AR-C67085MX), having an IC50 Of 2.5 nM against ADP-indu ced aggregation of human platelets. Compound 10e was the first very potent antagonist of the P-2T receptor, with a selectivity for that subtype of the P2 receptor family of >1000-fold. Further modification of the structure pr oduced compound 101 (AR-C69931MX) having an IC50 of 0.4 nM. In vivo, at max imally effective antithrombotic doses, there is little prolongation of blee ding time (1.4-fold), which is in marked contrast to the 5-6-fold found wit h GPIIb/lIIa antagonists.