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SC-54684A, an orally active antiplatelet drug now in clinical trial, is shown to be a potent, specific fibrinogen binding inhibitor that blocks platelet aggregation to a wide variety of known stimuli and has good bioavailability in animals.

This study was designed to evaluate the antithrombotic efficacy and bleeding propensity of a selective, small-molecule inhibitor of tissue factor/factor VIIa (TF/VIIa) in comparison to smallmolecule, selective inhibitors of factor Xa and thrombin in a nonhuman primate model of thrombosis. Acute, spontaneous thrombus formation was induced by electrolytic injury to the intimal surface of a femoral blood vessel, which results in thrombus propagation at the injured site. The TF/FVIIa inhibitor 3-amino-5-[1- [2-({4-[amino(imino)methyl]benzyl}amino)-2-oxoethyl]-3-chloro-5-(isopropylamino)-6-oxo-1,6-dihydropyrazin-2-yl]benzoic acid dihydrochloride (PHA-927F) was fully effective in prevention of thrombosis-induced vessel occlusion at a dose of 400 g/kg/min, i.v., in the arterial vasculature (femoral artery). Neither the effective dose nor multiples up to 4.4-fold the effective arterial plasma concentration elicited any significant effect on bleeding time or blood loss from either the bleeding time site or the surgical (femoral isolation) site. Smallmolecule inhibitors of factor Xa or thrombin were effective arterial antithrombotic agents; however, in contrast to the TF/ FVIIa inhibitor, they both elicited substantial increases in bleeding propensity at the effective dose and at multiples of the effective plasma concentration. These data indicate that TF/ VIIa inhibition effectively prevented arterial thrombosis with less impact on bleeding parameters than equivalent doses of factor Xa and thrombin inhibitors.The most common cause of mortality in the United States and Western countries is cardiovascular disease, predominantly associated with acute coronary syndromes consisting of unstable angina, myocardial infarction, and sudden death (Braunwald et al., 1989). Acute coronary syndromes are associated with acute thrombus formation, often as the result of rupture of the thin fibrous cap of a vulnerable plaque. Upon plaque rupture, platelet activation occurs followed by a cascade of coagulation reactions as tissue factor is exposed to soluble factor VIIa in the blood (Moreno et al., 1996).Tissue factor initiates the extrinsic pathway of blood coagulation and is the obligate cofactor for activation of zymogen coagulation factor VII to the serine protease factor VIIa. The tissue factor/factor VIIa complex (TF/VIIa) initiates coagulation by activating the physiological substrates factor IX and factor X, ultimately leading to thrombin generation and fibrin deposition. Tissue factor is a cell surface-expressed glycoprotein that is composed of a 219-amino acid residue extracellular domain, a single transmembrane sequence, and a short cytoplasmic domain (Edgington et al., 1991). Tissue factor is primarily expressed in the media and adventitia of blood vessels forming a hemostatic envelope that surrounds the vessel.Following plaque rupture or vascular damage, such as occurs in hypertension, atherosclerosis, diabetes, smoking, and interventional procedures, such as balloon angioplasty, tissue factor is exposed to the blood a...

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A key role has been established for platelet activation and thrombus formation in the pathogenesis of acute coronary syndromes, and restenosis after percutaneous interventions. Antiplatelet agents that have a wider spectrum of activity than aspirin, and clopidogrel would be expected to provide improved antithrombotic protection. Preclinical studies were used to predict clinical efficacy of orally active GPIIb/IIIa antagonists such as xemilofiban, sibrafiban, lefradafiban, and orbofiban. While clinical trials have shown potent and sustained platelet inhibition, outcomes of trials with these first generation GPIIb/IIIa compounds have been disappointing. The active moiety of orbofiban is a potent and specific inhibitor of fibrinogen binding to GPIIb/IIIa, leading to inhibition of platelet aggregation to a wide variety of agonists. Studies comparing inhibition of aggregation and bleeding suggest that chronic inhibition of platelet aggregation can be achieved without major bleeding side effects. Thrombus formation is prevented in canine models of thrombosis. Orbofiban is approximately 28% bioavailable with a t(1/2) of 18 hr. The high bioavailability, long half-life, and potential safety suggest orbofiban would be suitable for chronic oral administration. Clinical data demonstrate that orally administered orbofiban has the desired pharmacodynamic effect of inhibiting platelet aggregation but does not demonstrate clinical benefit when examined in large-scale trials.