New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors

Abstract

Currently approved platelet adenosine diphosphate (ADP) receptor antagonists target only the platelet P2Y12 receptor. Moreover, especially in patients with acute coronary syndromes, there is a strong need for rapidly acting and reversible antiplatelet agents in order to minimize the risk of thrombotic events and bleeding complications. In this study, a series of new P1,P4-di(adenosine-5′) tetraphosphate (Ap4A) derivatives with modifications in the base and in the tetraphosphate chain were synthesized and evaluated with respect to their effects on platelet aggregation and function of the platelet P2Y1, P2Y12, and P2X1 receptors. The resulting structure-activity relationships were used to design Ap4A analogs which inhibit human platelet aggregation by simultaneously antagonizing both P2Y1 and P2Y12 platelet receptors. Unlike Ap4A, the analogs do not activate platelet P2X1 receptors. Furthermore, the new compounds exhibit fast onset and offset of action and are significantly more stable than Ap4A to degradation in plasma, thus presenting a new promising class of antiplatelet agents.

Synergistic Inhibition of Both P2Y 1 and P2Y 12 Adenosine Diphosphate Receptors As Novel Approach to Rapidly Attenuate Platelet-Mediated Thrombosis

“…Moreover, GLS-409 did not affect hemodynamics in our rat and canine model, and was only associated with a moderate non-significant increase in median bleeding time in our canine model, while showing a fast plasma clearance. These findings, together with the previous data on its high plasma stability and reversibility of its antiplatelet effects, 22 suggest that GLS-409 could become a meaningful addition to the current pharmacological armamentarium in ACS. Presently, GLS-409 is undergoing late stage pre-clinical evaluation with a particular focus on the transition from GLS-409 to clinically-approved, oral P2Y 12 inhibitors with a goal of initiating human clinical testing in near future.…”

“…In these cases, the fast restoration of platelet function would be of great importance. Since GLS-409 has a much shorter plasma half-life than prasugrel and ticagrelor, 22, 33 its use may result in a significant reduction of serious bleeding events compared to the clinically approved, oral P2Y 12 inhibitors in the above-mentioned patient populations.…”

“…20, 21 In a subsequent study, a series of new Ap 4 A analogs, with modifications in the tetraphosphate chain, and/or 2-, or N 6 -positions in the base were synthesized and evaluated as platelet aggregation inhibitors, and with respect to their effects on platelet P2Y 1 , P2Y 12 , and P2X1 receptors. 22 The established structure-activity relations were used to design Ap 4 A analogs which potently inhibit human platelet aggregation by simultaneously targeting platelet P2Y 1 and P2Y 12 ADP receptors but, unlike Ap 4 A, do not activate the platelet P2X1 receptor. The new Ap 4 A analogs can be administered intravenously and act reversibly, and they show significantly higher plasma stability than Ap 4 A.…”

“…The new Ap 4 A analogs can be administered intravenously and act reversibly, and they show significantly higher plasma stability than Ap 4 A. 22 Because of their unique and reversible mechanism of action, their route of administration, the fast onset of their antiplatelet effect, and their short plasma half-life, these new compounds may be beneficial in clinical situations where a high atherothrombotic risk and an increased bleeding risk coincide. Accordingly, they are envisioned as a future treatment option in the initial phase of ACS.…”

Update of P2Y receptor pharmacology: IUPHAR Review 27

“…Ticagrelor has been reported to act as an inverse agonist under some experimental conditions (Aungraheeta et al, 2016; Garcia et al, 2019). A series of novel analogues of Ap 4 A blocks P2Y 12 receptors at nanomolar concentrations; one of the most potent derivatives was compound 37 (Yanachkov et al, 2016).…”