Platelets are central to thrombus formation, the leading cause of global mortality. PAR4 (protease-activated receptor 4) is a G-protein coupled receptor. Meanwhile, PAR4 together with PAR1 is responsible for thrombin-mediated platelet activation and aggregation. However, PAR4 plays a distinct role from PAR1 in thrombin-mediated human platelet activation. First, PAR4 has a 20- to 70-fold slower rate of activation versus PAR1, and most of the integrated calcium signal is sustained. Second, PAR4 activation occurs after adenosine diphosphate secretion and may stabilize platelet aggregates. Third, the distinct ability of PAR4 AP to induce platelet spreading may contribute to the formation of a stable thrombus. Therefore, PAR4 has potential to be as an antiplatelet target. BMS-986120, a first-in-class oral and reversible PAR4 antagonist, selectively binds to PAR4 as a potent and highly efficacious antithrombotic reagent.
BMS-986120 is a first-in-class oral and reversible protease-activated receptor 4 (PAR4) antagonist, with IC50s of 9.5 nM and 2.1 nM in human and monkey blood, respectively.
Consistent with its high binding affinity, BMS-986120 inhibits PAR4 AP-induced cellular calcium mobilization in HEK cells. It shows both high potency (IC50 = 0.56 nM) and selectivity. In addition, BMS-986120 fully inhibits PAR4 AP-induced signaling via multiple pathways, including G protein activation, β-arrestin 2 recruitment, and extracellular signal–regulated kinase 1/2 activation. Furthermore, BMS-986120 fully inhibits human PRP aggregation in response to g-thrombin with an IC50 of 7.3 nM. It comparably inhibits PA induced by PAR4-AP in human and monkey blood in vitro (IC50 of 9.5±2.7 and 2.1±0.4 nM, respectively).
BMS-986120 is highly effective in preserving vascular patency during the induction of occlusive thrombosis in monkeys. BMS-986120 produces a dose-dependent preservation of flow during thrombosis. At 1 mg/kg, BMS-986120 maintains blood flow almost at the control baseline and prevented vascular occlusion in all animals. It also decreased thrombus weight in a dose-dependent manner. The IC50 is 6 nM.
In sunmmary, BMS-986120 has potential as an antiplatelet agent and currently under clinical investigation.
Wong PC, et al. Sci Transl Med. 2017 Jan 4;9(371).