New P2Y ₁₂ Inhibitors

Abstract

A denosine diphosphate (ADP) plays a key role in the genesis of physiological platelet-rich hemostatic plugs and of pathological arterial thrombi. 1 The transduction of the ADP signal involves its interaction with 2 platelet receptors, the G q -coupled P2Y 1 receptor and the G i -coupled P2Y 12 receptor, which belong to the family of purinergic P2 receptors. Concomitant activation of both the G q and G i pathways by ADP is necessary to elicit normal platelet aggregation. 2 In addition to its role in ADP-induced platelet aggregation, P2Y 12 (Figure 1) also mediates the potentiation of platelet secretion induced by strong agonists, which is independent of the formation of large aggregates and thromboxane A 2 synthesis 2 ; the stabilization of thrombin-induced platelet aggregates 2 ; shear-induced platelet aggregation 2 ; and the inhibition of the antiplatelet effects of the natural regulator of platelet function, prostacyclin. 3 In contrast to P2Y 1 , P2Y 12 has a very selective tissue distribution, making it an attractive molecular target for therapeutic intervention. Indeed, P2Y 12 is the target of efficacious antithrombotic agents. 1

Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses

“…To date only two P2 receptor antagonist are marketed: the irreversible P2Y 12 receptor antagonist clopidogrel (Plavix®), which is used as an antithrombotic agent in patients with atherosclerotic vascular disease [234] and another orally active but reversible antagonist of P2Y 12 , Ticagrelor (Brilinta®), which showed to even have a greater efficacy in reducing cardiovascular death compared with clopidogrel [235].…”

P2 receptors and platelet function

“…Competitive P2Y 12 antagonists cangrelor (AR-C69931MX) and ticagrelor (AZD6140) are in various phases of development, the latter being orally active while cangrelor requires intravenous administration [45, 116,117]. Theoretically, use of such molecules would have an advantage mainly in acute situations like myocardial infarction, where fast blockade of the ADP receptor should be beneficial as compared to the delayed action of thienopyridine compounds.…”

The platelet P2 receptors in inflammation

“…Recently, it was shown that LTE 4 enhances inflammatory cell recruitment in lungs of sensitized mice, which is abrogated by platelet depletion, by treatment with the anti-P2Y 12 thienopyridine drug clopidogrel (69), and in mice lacking P2Y 12 , but not in mice lacking CysLT 1 R and CysLT 2 R (70). Moreover, intranasal administration of LTC 4 in sensitized mice before ovalbumin challenges potentiated the recruitment of eosinophils in the bronchoalveolar lavage, which was dependent on CysLT 2 R, but also on P2Y 12 and platelets (71).…”