Recent developments in the field of haemostasis and
thrombosis highlighted the crucial role of the
tissue factor/
factor VIIa complex (TF/FVIIa) in the initiation of coagulation processes. Nowadays,
anticoagulant therapies involving
heparin or
coumarin derivatives,
thrombin or
factor Xa inhibitors are generally associated with side effects such as
bleeding and
thrombocytopenia. In this context, the inhibition of TF, FVIIa and their complex by efficient antithrombotic drugs represents a new strategy to reduce this
bleeding and to prevent
thrombosis events. Moreover, TF/FVIIa inhibition is shown to be useful in the treatment of biological processes independent of the clotting cascade such as angiogenesis and
cancer. Among the natural and genetically engineered TF/FVIIa inhibitors,
injections of the
recombinant protein rNAPc2 show clinical improvements, such as reduced
bleeding and
thromboembolism, over classical drugs used in the
therapy of coronary angioplasty and hip or knee replacement surgery. The knowledge of the 3D-structure of TF/FVIIa complex and examination of co-crystal data of some drugs bound to this complex led to the design and synthesis of numerous TF/FVIIa inhibitors. Among them, the p-amidinophenylurea 18 (Ki = 0.027 microM), the
pyrimidinones PHA-927 (30, IC50 = 0.016 microM) and PHA-798 (31, IC50 = 0.014 microM) and the pyridinone 37 (IC50 = 0.052 microM) are highly potent inhibitors of the TF/FVIIa complex, deprived of activity towards
thrombin (IC50 > 30-100 microM) and
factor Xa (IC50 > 10-100 microM), other
proteases involved in the coagulation cascade. Both
pyrimidinones prevent arterial
thrombosis in non-human primate models of
thrombosis and represent a safe approach to anti-thrombotic
therapy in patients with cardiovascular risk factors.