Vorapaxar is a potent PAR1 inhibitor and antiplatelet that was completed in phase III clinical trial.
PAR1 is one of the 4 thrombin receptor types that belong to G-protein coupled receptors super family. 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.
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. In human plasma enriched with platelets, Vorapaxar was able to inhibit the aggregation of platelet with an IC50 value of 47 nM. 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. 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) .
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 , 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%.
. Chackalamannil S & XIA, Y. Thrombin receptor (PAR-1) antagonists as novel antithrombotic agents. Expert Opinion on Therapeutic Patents, 2006.16:493-505.
. 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.
|Physical Appearance||A solid|
|Storage||Store at -20°C|
|Solubility||≥24.65mg/mL in DMSO|
|Chemical Name||ethyl N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethenyl]-1-methyl-3-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-benzo[f]benzofuran-6-yl]carbamate|
|Shipping Condition||Evaluation sample solution : ship with blue ice.All other available size: ship with RT , or blue ice upon request|
|General tips||For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.|
|Description||Vorapaxar (SCH 530348) is a potent and orally active antagonist of thrombin receptor (PAR-1) with a Ki value of 8.1 nM.|
|IC50||8.1 nM (Ki)|