The Discovery of Vorapaxar (SCH 530348), a Thrombin Receptor (Protease Activated Receptor-1) Antagonist with Potent Antiplatelet Effects - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 47

There are plausible explanations for the absence of significant bleeding that is
noted for the thrombin receptor antagonists in preclinical animal models and in
the TRA-PCI study. Although proteolytic activation of the thrombin receptor
is the most potent mechanism of platelet stimulation, other platelet activation
mechanisms that remain intact are perhaps sucient for normal hemostasis.
Thrombin-mediated platelet activation therefore might represent a more
pathologically-relevant platelet activation mechanism in the context of a major
vascular injury, such as rupture of an atherosclerotic plaque or PCI procedures.
In a recent study in PAR4 / mice, Furie and Coughlin have demonstrated,
using real-time digital fluorescence microscopy, that platelet activation by
thrombin is necessary for thrombus growth, but not for primary hemostasis. 78
During laser-induced thrombosis, juxtamural platelet accumulation immedi-
ately after laser injury was not affected in PAR4 / mice. However, subsequent
growth of platelet thrombi was markedly diminished in PAR4 / mice. Also,
fibrin generation was preserved in the knockout mice. The conclusion from
these studies is that a thrombin receptor antagonist could produce potent
antiplatelet effect without increased bleeding. The ongoing clinical studies will
be needed to validate the long-term sustainability of the anticipated safety
margins and ecacy for thrombin receptor antagonists.
Acknowledgement
The author acknowledges the support of Dr. William J. Greenlee. Also
acknowledged are contributions from Drs. Mariappan Chelliah, Martin
Clasby, Yan Xia, Yuguang Wang, and Mr. Keith Eagen. Their individual
contributions have been cited in the reference section.
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