Vorapaxar

Vorapaxar is a potent PAR1 inhibitor and antiplatelet that was completed in phase III clinical trial[1].

PAR1 is one of the 4 thrombin receptor types that belong to G-protein coupled receptors super family[1]. By binding to thrombin, the N-terminal at the arginine 41 and serine 42 bond of PAR1 on platelet surface can be enzymatically cleaved, resulting in the activation of platelet and subsequent hemostasis process[1].

Vorapaxar is an ethyl-carbamate molecule that derived from natural himbacine and has been determined to be a selective PAR 1 inhibitor through direct binding[2]. In human plasma enriched with platelets, Vorapaxar was able to inhibit the aggregation of platelet with an IC50 value of 47 nM[2]. In addition, vorapaxar is able to inhibitthe platelet aggregation that triggered by the addition of thrombin receptor activating peptide with an IC50 value of 25 nM[2]. At the same time, however, vorapaxar does not interfere thrombin’s enzymatic activity on fibrin formation or thromboxane A2 receptors-induced platelet aggregation, as was demonstrated by its inability to inhibit platelet aggregation that induced by the addition of 9,11-dideoxy-11R,9R-epoxymethanoprostaglandin F2R (a thromboxane mimetic) [1].

In vivo, oral administration of 0.1 mg/kg of Vorapaxar completely inhibited the platelet aggregation monkey model for 24 hrs. In phase III clinical trial that involved 26,449 patients [1], administration of vorapaxar (2.5 mg/day) reduced the occurrence of cardiovascular death or ischemic events compared with placebo group by a statistically significant 1.2%[1].

References:
[1].  Chackalamannil S & XIA, Y. Thrombin receptor (PAR-1) antagonists as novel antithrombotic agents. Expert Opinion on Therapeutic Patents, 2006.16:493-505.
[2].  Chackalamannil S, Wang Y, Greenlee W J et al. 2008. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J Med Chem, 2008,51: 3061-3064.