Mechanism of Thrombin Receptor Activation

A high-resolution crystal structure of vorapaxar-bound to PAR-1 has been recently published [22]. The structure reveals that the vorapaxar binding pocket. 

Preclinical Data Supporting the Antiplatelet Effect of Thrombin Receptor Antagonists 

As mentioned above, due to the absence of PAR-1 receptors in mouse and rat platelets, nonhuman primate models have been often used to test the antiplatelet effect of PAR-1 antagonism. In vivo studies carried out by PAR-1 antagonists of peptide and nonpeptide origin showed inhibition of platelet-rich thrombus formation in a baboon thrombosis model and in a guinea pig thrombosis model, suggesting the promise of a PAR-1 antagonist for inhibiting arterial thrombosis [28,29]. In another important study, an antibody to the PAR-1 N-terminus 

Lead Generation from Himbadne-derived Thrombin Receptor Antagonist Hit 

The lactone ring is essential for PAR-1 activity. The lactone ring does not remain opened as the carboxylic acid-alcohol because it spontaneously cyclizes, presumably due to the Thorpe-Ingold effect exerted by the methyl group. Reduced versions of the lactone, such the fused tetrahydrofuran and diol (not shown) are far less active. The C3 methyl group is optimal, whereas the C3 

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Figure 19.2 The tethered ligand mechanism of thrombin receptor activation. Thrombin binds to the extracellular domain of the receptor and cleaves it at Arg -Ser. The newly generated serine N-terminus binds intramolecularly to the receptor, triggering cellular activation.

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