Impact of Aspirin Dosing on the Effects of P2Y12 Inhibition in Patients with Acute Coronary Syndromes

The discovery of the antiplatelet effect of low-dose aspirin led to the hugely successful strategy of dual antiplatelet therapy in patients with acute coronary syndromes (ACS). Increasing the dose of aspirin beyond 75-100 mg has never been shown to offer additional efficacy in ACS patients but could possibly increase the risk of bleeding. In the Platelet Inhibition and Patients Outcome (PLATO) study, higher doses of aspirin appeared to neutralise the additional benefit of the potent P2Y12 inhibitor ticagrelor compared to clopidogrel (Circulation 124: 544-554, 2011). However, higher doses of aspirin have not been shown to have an adverse interaction with the potent P2Y12 inhibition provided by prasugrel and double-dose clopidogrel (Journal of the American College of Cardiology, 2013, in press; N Engl J Med 363: 930-942, 2010). This potentially suggests that the mechanism for this interaction is not related to the inhibition of platelet P2Y12 receptors or could simply be a chance finding.</p

Pharmacochemistry of the platelet purinergic receptors

Platelets contain at least five purinergic G protein-coupled receptors, e.g., the pro-aggregatory P2Y1 and P2Y12 receptors, a P2Y14 receptor (GPR105) of unknown function, and anti-aggregatory A2A and A2B adenosine receptor (ARs), in addition to the ligand-gated P2X1 ion channel. Probing the structure–activity relationships (SARs) of the P2X and P2Y receptors for extracellular nucleotides has resulted in numerous new agonist and antagonist ligands. Selective agents derived from known ligands and novel chemotypes can be used to help define the subtypes pharmacologically. Some of these agents have entered into clinical trials in spite of the challenges of drug development for these classes of receptors. The functional architecture of P2 receptors was extensively explored using mutagenesis and molecular modeling, which are useful tools in drug discovery. In general, novel drug delivery methods, prodrug approaches, allosteric modulation, and biased agonism would be desirable to overcome side effects that tend to occur even with receptor subtype-selective ligands. Detailed SAR analyses have been constructed for nucleotide and non-nucleotide ligands at the P2Y1, P2Y12, and P2Y14 receptors. The thienopyridine antithrombotic drugs Clopidogrel and Prasugrel require enzymatic pre-activation in vivo and react irreversibly with the P2Y12 receptor. There is much pharmaceutical development activity aimed at identifying reversible P2Y12 receptor antagonists. The screening of chemically diverse compound libraries has identified novel chemotypes that act as competitive, non-nucleotide antagonists of the P2Y1 receptor or the P2Y12 receptor, and antithrombotic properties of the structurally optimized analogues were demonstrated. In silico screening at the A2A AR has identified antagonist molecules having novel chemotypes. Fluorescent and other reporter groups incorporated into ligands can enable new technology for receptor assays and imaging. The A2A agonist CGS21680 and the P2Y1 receptor antagonist MRS2500 were derivatized for covalent attachment to polyamidoamine dendrimeric carriers of MW 20,000, and the resulting multivalent conjugates inhibited ADP-promoted platelet aggregation. In conclusion, a wide range of new pharmacological tools is available to control platelet function by interacting with cell surface purine receptors