Ticagrelor (AZD6140) is the first reversibly binding oral P2Y12 receptor antagonist that blocks ADP-induced platelet aggregation. Unlike thienopyridines, which irreversibly bind to the P2Y12 receptor for the lifetime of the platelet, ticagrelor binds reversibly to the receptor and exhibits rapid onset and offset of effect, which closely follow drug exposure levels. Animal models indicate greater separation between antithrombotic effects and bleeding effects with ticagrelor than with thienopyridines. Unlike the thienopyridines, ticagrelor does not require metabolic activation. It is quickly absorbed and exhibits a rapid antiplatelet effect, with higher and more consistent levels of inhibition of platelet aggregation (IPA) being maintained across the dosing interval than with clopidogrel. IPA levels decline with plasma drug levels after discontinuation of dosing. In the phase II DISPERSE-2 trial of 990 patients with non-ST-elevation acute coronary syndromes (ACS), ticagrelor treatment with 90 mg and 180 mg twice daily showed comparable rates of major and minor bleeding compared with clopidogrel 75 mg while there were numerically fewer myocardial infarctions. Ticagrelor resulted in greater IPA in clopidogrel-naïve patients and produced substantial additional reductions in platelet aggregation activity in patients pretreated with clopidogrel. Ticagrelor treatment was well tolerated in DISPERSE-2, and discontinuation rates were comparable to those observed for clopidogrel. An increased risk of mild to moderate dyspnea and mostly asymptomatic ventricular pauses were observed in phase II studies. The mechanisms for these effects are currently being investigated. The efficacy and safety of ticagrelor are being further evaluated in the phase III PLATO trial, involving approximately 18,000 patients with ACS, including both ST-elevation and non-ST-elevation ACS.

Ticagrelor inhibits cellular adenosine uptake selectively via ENT1 inhibition at concentrations of clinical relevance. However, the low-binding affinity and functional inhibition of adenosine receptors observed with ticagrelor or its metabolites indicate that they possess a negligible adenosine-like activity at clinically relevant concentrations.

human P2Y 12 independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost 2009; 7: 1556À65.Summary. Background: P2Y 12 plays an important role in regulating platelet aggregation and function. This receptor is the primary target of thienopyridine antiplatelet agents, the active metabolites of which bind irreversibly to the receptor, and of newer agents that can directly and reversibly modulate receptor activity. Objective: To characterize the receptor biology of the first reversibly binding oral P2Y 12 antagonist, ticagrelor (AZD6140), a member of the new cyclopentyltriazolopyrimidine (CPTP) class currently in phase III development. Methods: Ticagrelor displayed apparent non-competitive or insurmountable antagonism of ADP-induced aggregation in human washed platelets. This was investigated using competition binding against [ 12 is targeted by ticagrelor via a mechanism that is noncompetitive with ADP, suggesting the existence of an independent receptor-binding site for CPTPs.

Ticagrelor enhanced adenosine-induced CBFV and the sensation of dyspnea in these healthy male subjects via an adenosine-mediated mechanism. (Study to Assess the Effect of Ticagrelor on Coronary Blood Flow in Healthy Male Subjects; NCT01226602).

An important role for adenosine diphosphate (ADP)-induced platelet activation and aggregation was proposed more than 40 years ago. The clinical use of clopidogrel, a prodrug of an irreversible P2Y (12) antagonist, has further proved the relevance of inhibiting signaling via the platelet-specific P2Y (12) ADP receptor in the prevention of cardiovascular events. Pharmacological studies at AstraZeneca R&D Charnwood have identified direct, selective, and competitive P2Y (12) antagonists, including cangrelor (also known as AR-C69931MX), which is suitable for intravenous administration, and AZD6140, which is suitable for oral administration. In preclinical use, these compounds predictably and effectively inhibited platelet aggregation without significant increases in bleeding time. In clinical use, these compounds may have significant advantages over current antiplatelet agents. This article summarizes preclinical and clinical data on cangrelor and AZD6140 and discusses the potential of these compounds as novel antiplatelet therapies.