An amidrazonophenylalanine derivative,
LB30057, inhibits the catalytic activity of
thrombin potently by interaction with the active site of
thrombin, and has high water solubility. In the present study, we evaluated the effect of
LB30057 on the
biological activities of
thrombin at various tissues, and determined whether
thrombin inhibition by
LB30057 could reduce the incidence of occlusive
thrombosis in an in vivo animal model. Treatment with
LB30057 to human plasma prolonged clotting times in a concentration-dependent manner.
LB30057 suppressed significantly
thrombin-induced
phosphatidylserine (PS) exposure in platelets, suggesting that
LB30057 could inhibit blood coagulation accelerated by PS exposure. In human platelets, soluble
thrombin- and clot-induced platelet aggregation was inhibited by
LB30057 potently. Consistent with this finding,
LB30057 showed concentration-dependent inhibitory effects on
serotonin secretion and
P-selectin expression induced by
thrombin in platelets. In the blood vessel isolated from the guinea pig, treatment with
LB30057 resulted in a concentration-dependent inhibition of
thrombin-induced vascular contraction. In vivo study revealed that
LB30057 following
oral administration significantly increased the time to occlusion and improved carotid arterial patency using rat
carotid artery thrombosis model. All these results suggest that
LB30057 is a potent inhibitor of
biological activities of
thrombin at various target tissues and, therefore, might be developed as an
antithrombotic agent for treatment and prevention of thrombotic diseases.