Protease-activated receptor 1 (PAR1) is a thrombin-activated receptor that contributes to inflammatory responses at mucosal surfaces[5]. Vorapaxar is an orally effective thrombin receptor (par-1) antagonist with a Ki value of 8.1 nM in cell-free assay[6]. The compound showed potent inhibition of thrombin-induced platelet aggregation with an IC50 of 47 nM and haTRAP-induced platelet aggregation with an IC50 of 25 nM, whereas it showed no inhibition of platelet aggregation induced by other agonists such as ADP, collagen, and a PAR-4 agonist peptide[6]. In additional functional assays, vorapaxar inhibited thrombin-induced calcium transient in human coronary artery smooth muscle cells (HCASMC) with a Ki of 1.1 nM, it also inhibited thrombin-stimulated thymidine incorporation in HCASMC with a Ki of 13 nM[6]. Pharmacokinetic profiling of vorapaxar was done in rat and monkey models. Following oral administration, vorapaxar was well absorbed in rat (68%; 10 mg/kg) and in monkey (82%; 1 mg/kg) models. Tmax was observed at about 3 h in rats and 1 h in monkeys. The elimination half-life was 5.1 h in rats and 13 h in monkeys. The oral bioavailability was 33% in rats and 86% in monkeys[6]. In an ex vivo cynomolgus monkey model of platelet aggregation, vorapaxar was 30 times more potent than the initial development candidate in the series, showing complete obliteration of agonist induced platelet activation at 0.1 mg/kg with >24 h duration of activity (versus comparable efficacy at 3 mg/kg for the initial candidate) [6].
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