3.2.2. Inhibition of Phosphoinositide 3-Kinase Beta (PI3Kβ)

PI3Kβ is a lipid kinase that acts as an important mediator in the signal transduction downstream of the activation of P2Y12, GPIIb/IIIa, GPVI, PAR, and GPIb and plays a pivotal role in platelet aggregation and thrombus stability.

Based on the specific PI3Kβ inhibitor, TGX-221, which has only been tested in preclinical studies, a new molecule with better pharmacological properties has been developed, AZD-6482. This drug has shown in a phase I trial to moderately inhibit ADP- and collageninduced platelet aggregation, particularly under high shear stress conditions with only mild prolonged bleeding time [157]. In another phase I study, the combination of AZD-6482 with ASA provided greater platelet inhibition compared to DAPT with ASA and clopidogrel without translating into prolonged bleeding times [158]. A new phase II trial (STARS) is planned to test the safety and tolerability of this drug in reperfusion for stroke (NCT05363397).

## 3.2.3. Selatogrel: The New Antagonist of the P2Y12 Receptor

Selatogrel (ACT-246475) is a new potent, reversible, and selective inhibitor of the P2Y12 platelet receptor. Its efficacy and safety have already been confirmed in phase I and II clinical trials. In contrast to the currently used P2Y12 inhibitors (i.e., oral or intravenous administration), selatogrel is administered subcutaneously, overcoming potential pharmacokinetic limitations of other P2Y12 inhibitors, including the delay of absorption and lack of enteral access for administration with oral formulations; the need for intravenous access with cangrelor; or the need for metabolization (e.g., clopidogrel and prasugrel) to be ideal in the critical 3-h window during an ACS [159]. Additionally, selatogrel seems to have a lower bleeding risk profile than clopidogrel or ticagrelor. A study performed in mice showed that the stability of hemostatic seals was undisturbed in the presence of selatogrel, unlike clopidogrel or ticagrelor. The authors suggested that the mechanism underlying the differences in blood loss profiles among these P2Y12 receptor antagonists was related to offtarget interference with endothelial and neutrophil cells and fibrin-mediated stabilization of hemostatic seals [160]. Subsequently, phase I and phase II clinical trials have confirmed that selatogrel provides sustained and reversible P2Y12 platelet inhibition with an acceptable safety profile [159]. A phase III clinical trial is currently underway (NCT04957719).

## 3.2.4. New P2Y1 Receptor Antagonists

Besides the P2Y12 receptor, human platelets express another purinergic ADP receptor named P2Y1. The binding of ADP to P2Y1 initiates platelet aggregation response which may be reverted, while P2Y12 activation leads to irreversible platelet aggregation. Therefore, complete platelet aggregation requires a complex interplay and coactivation of both P2Y1 and P2Y12 receptors [161]. Following this assumption, several P2Y1 inhibitors have been developed, though so far, they have only been tested in animal models, as detailed in Table 5 [162].
