title: Modulators of the coagulation cascade: focus and recent advances in inhibitors of tissue factor, factor VIIa and their complex.
abstract: 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.
authors.affiliation: Department of Pharmacy, University of Namur, FUNDP, 61 rue de Bruxelles, 5000 Namur, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Frédérick
authors.forename: L
authors.initials: L
authors.lastname: Pochet
authors.forename: C
authors.initials: C
authors.lastname: Charlier
authors.forename: B
authors.initials: B
authors.lastname: Masereel
mesh_terms: D000595:Amino Acid Sequence; D000925:Anticoagulants / Q000737:chemistry*; D001777:Blood Coagulation; D019774:Blood Coagulation Factor Inhibitors / Q000737:chemistry*; D015942:Factor VIIa / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D016415:Sequence Alignment; D015842:Serine Proteinase Inhibitors / Q000737:chemistry; D013925:Thromboplastin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D019774:Blood Coagulation Factor Inhibitors; D010455:Peptides; D015842:Serine Proteinase Inhibitors; D013925:Thromboplastin; D015942:Factor VIIa