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H
2
N
NH
H
2
N
HN
NH
Cl
NH
2
HN
Cl
O
N
N
O
O
Ph
O
N
N
BnHN
N
N
N
N
H
H
H
NH
2
O
O
O
O
O
2
(RWJ 58259)
NH
NH
2
F
1
F
O
F
Figure 2.3
Examples of early peptide and peptidomimetic thrombin receptor antago-
nists.
vascular injury model.
58
The compound was administered intravenously and
the degree of vessel occlusion caused by electrolytic injury-induced thrombus in
each carotid artery was characterized. Compound 2 significantly reduced
occlusion in the vessels of all animals; of note that these vessels were completely
occluded under experimental conditions in the absence of drug. In the drug-
treated group, not only was the thrombus size reduced, but the composition of
the thrombus indicated a switch from platelet-rich thrombi to platelet-depleted
thrombi, demonstrating the antiplatelet property of a PAR-1 antagonist. In a
related study in rat, compound 2 showed significant reduction of neointima
thickness in a rat restenosis model after perivascular administration, suggesting
the potential utility of a thrombin receptor antagonist to treat vascular pro-
liferative disorders such as restenosis.
42
As described below, more recent studies using potent PAR-1 antagonists in
non-human primate thrombosis models have corroborated the outcome of
these earlier studies and established the therapeutic potential of PAR-1
antagonists as promising antithrombotic agents.
59
By selectively inhibiting
PAR-1-mediated platelet activation, a PAR-1 antagonist should exhibit strong
antiplatelet action under conditions in which thrombin-stimulated platelet
activation is important. A PAR-1 antagonist is specific for thrombin-mediated
platelet aggregation and it would not interfere with platelet activation by other
platelet receptors needed for normal hemostasis. Additionally, fibrin generation
by thrombin would not be affected, keeping the normal coagulation processes
intact. For these reasons, a PAR-1 antagonist is expected to give an improved
safety margin with regard to any hemorrhagic side effect, which is a compli-
cating factor for the current antithrombotic therapy.
2.4.3 Small-molecule Thrombin Receptor Antagonists
There has been considerable progress in the discovery of orally active small-
molecule thrombin receptor antagonists.
60
Some examples of early small-
molecule thrombin receptor antagonists are shown in Figure 2.4. In the radi-
oligand binding assay using [
3
H]-TRAP, these compounds showed promising
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