Chapter 2: The Discovery of Vorapaxar (SCH 530348), a Thrombin Receptor (Protease Activated Receptor-1) Antagonist with Potent Antiplatelet Effects

The coagulation and platelet activation mechanisms synergize in hemostasis and thrombosis. Thrombin plays a key dual role in these by generation of fibrin from fibrinogen and by activation of platelets via protease activated receptors (PARs). Human platelets contain the high affinity PAR-1, also know as the thrombin receptor, and the low affinity PAR-4. Among the various platelet activating mechanisms, PAR-1 stimulation is the most potent one, and as such, a PAR-1 antagonist is expected to confer potent antiplatelet effects. Additionally, a PAR-1 antagonist is expected to produce less bleeding side effect than currently available antithrombotic agents, since fibrin generation would be unaffected, and platelet activation by other mechanisms needed for normal hemostasis would be maintained.

SCH 530348 is a potent thrombin receptor antagonist that was discovered by optimization of a lead derived from the natural product himbacine. It is a competitive antagonist of PAR-1 with a Ki of 8.1 nM and it was highly potent in multiple functional assays. In a preclinical ex vivo platelet aggregation model in cynomolgus monkeys, SCH 530348 showed complete and sustained inhibition of platelet aggregation for greater than 24 hours after an oral administration of 0.1 mg/kg. In phase I clinical trials, SCH 53048 demonstrated excellent safety and tolerability, and exhibited potent pharmacodynamic effects in human plasma. In a phase II clinical trial (TRA-PCI) in patients who underwent non-emergent percutaneous coronary intervention, SCH 530348 was not associated with increased TIMI major plus minor bleeding when compared with placebo, and therefore met its primary end point. For the secondary outcome endpoint, SCH 530348 was associated with a numerical reduction in periprocedural myocardial infarction and an overall reduction in arterial thrombotic events. SCH 530348 is currently undergoing two large Phase III studies in patients with acute coronary syndrome (TRA*CER) and in patients who are at risk of atherothrombotic events (TRA*2P).