This program is focused on the development of a small-molecule tissue factor/factor Vlla (TF/FVIla) inhibitor with unique anti-inflammatory properties as a novel therapeutic agent for the treatment of unstable angina. The aims involve testing the effects of BCX-3607, the TF/FVIla inhibitor, in diverse animal models that mimic atherosclerotic disease progression and acute coronary events. Atherosclerosis is an inflammatory process characterized by elevations in pro-inflammatory cytokines and the acute phase reactant C-reactive protein (CRP). CRP concentration is perhaps the most accurate long-term predictor of adverse events and its expression is induced by the cytokine interleukin (IL)-6. BCX-3607 not only inhibits the principal catalyst of the extrinsic pathway of blood coagulation, TF/FVIla, but it also reduces IL-6 levels in a mouse model of endotoxemia. Thus, TF/FVIla enzymatic activity could be linked with CRP production via IL-6. The first objective is to determine the anti-inflammatory effect of BCX-3607 in CRP transgenic (CRPtg) mice by monitoring IL-6, CRP, and serum amyloid P concentrations. Serum levels of these biomarkers will be determined at various times after the BCX-3607 dosing of lipopolysaccharide-treated CRPtg mice. Further objectives include determining the antithrombotic properties of BCX-3607 in a CRPtg mouse model of angioplasty guide-wire injury, a model that produces accelerated vessel occlusion. The antithrombotic properties of BCX-3607 will also be tested in a rabbit model of carotid artery stenosis and endothelial injury. In this unstable angina model, BCX-3607 will be infused at different doses and efficacy will be determined by the effects on prothrombin time, activated partial thromboplastin time, platelet aggregation, and cyclic flow variations measured by Doppler flow. In a second arm of this study, the duration of action of the antithrombotic effects of BCX-3607 will be determined. Another objective is to determine the effects of BCX- 3607 on in vivo thrombosis and neointimal formation by performing balloon-induced arterial injury in rabbits and pigs. Once a dose-response is defined for BCX-3607 against procoagulant activity on the luminal surface of injured aortas, arteries will be examined for neointimal thickening and stenosis one month after injury. Together, these models will help determine the in vivo anti-inflammatory and antithrombotic properties of BCX-3607, a potential agent for the treatment of acute coronary syndromes.
Thesaurus Terms: acute phase protein, coronary disorder, drug design /synthesis /production, drug screening /evaluation, enzyme activity, enzyme complex, small molecule, thromboplastin amyloid protein, biomarker, disease /disorder model, inflammation, interleukin 6, lipopolysaccharide, protein metabolism, restenosis, thrombosis enzyme linked immunosorbent assay, genetically modified animal, high performance liquid chromatography, laboratory mouse, laboratory rabbit, mass spectrometry, swine, ultrasound blood flow measurement
