Novel P2T receptor antagonists, such as compound 10l, potently inhibited ADP-induced platelet aggregation (IC50 0.4 nM) with minimal prolongation of bleeding time compared to GPIIb/IIIa antagonists.
Novel P2T receptor antagonists potently inhibit platelet aggregation with significantly less prolongation of bleeding time compared to GPIIb/IIIa antagonists in preclinical models.
The platelet P2T 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 P2T receptor antagonist. Modification of the polyphosphate side chain to prevent breakdown to the agonist adenosine diphosphate (ADP) and substitution of the adenine moiety to enhance affinity and selectivity for the P2T receptor led to the identification of 10e (AR-C67085MX), having an IC50 of 2.5 nM against ADP-induced aggregation of human platelets. Compound 10e was the first very potent antagonist of the P2T receptor, with a selectivity for that subtype of the P2 receptor family of >1000-fold. Further modification of the structure produced compound 10l (AR-C69931MX) having an IC50 of 0.4 nM. In vivo, at maximally effective antithrombotic doses, there is little prolongation of bleeding time (1.4-fold), which is in marked contrast to the 5-6-fold found with GPIIb/IIIa antagonists.
Ingall et al. (Fri,) conducted a other in Platelet aggregation. P2T receptor antagonists (compounds 10e and 10l) vs. GPIIb/IIIa antagonists was evaluated on ADP-induced aggregation of human platelets and bleeding time prolongation. Novel P2T receptor antagonists, such as compound 10l, potently inhibited ADP-induced platelet aggregation (IC50 0.4 nM) with minimal prolongation of bleeding time compared to GPIIb/IIIa antagonists.