The prevention of the occurrence and reoccurrence of myocardial infarction, stroke, PAOD and pulmonary embolism remains a pressing clinical priority. Well over 12.5 million people in the US suffer from one or more of these conditions, resulting in approximately 1 million deaths each year and an annual health care expenditure of over $US100 billion. First line therapy for these conditions includes the use of anticoagulants, a market currently approaching $US6 billion per year. Unfortunately many anticoagulants in current use suffer a number of limitations including a high incidence of serious or dose limiting hemorrhage, and in the case of heparin, heparin-induced-thrombocytopenia and thrombosis syndrome. The development of anti-coagulants with a lower risk of hemorrhage is thus required. Tissue factor (TF) is the essential cofactor for the coagulation protease factor VIIa (FVIIa). The role of TF in thrombotic diseases is becoming increasingly evident, and in particular inhibition of TF/FVIIa activity could be important following exposure of TF to blood subsequent to plaque rupture or vessel damage. One of the principal roles of the TF/FVIIa complex is to activate Factor X (FX) initiating the coagulation cascade and the inhibition of this step of the cascade could offer antithrombotic activity with a reduced risk of bleeding. Nycomed researchers have previously reported that a cyclic dodecapeptide sequence of FVII inhibited TF-dependent FX activation. The biological activity was localized to the tripeptide motif, Glu-Gln-Tyr, and a cyclic analog of this motif, Cys-Glu-Gln-Tyr-Cys (PN7051) has now been synthesized. PN7051 is a dose-dependent inhibitor of TF-dependent FX activation and coagulation of plasma with IC50 values of 10+/-2 microM and 1.3+/-0.2 mM, respectively. It shows inhibitory efficacy on acute thrombus formation in an ex vivo model of human thrombosis using native blood. Fibrin deposition, platelet-fibrin adhesion, platelet-thrombus formation, and thrombin-antithrombin complex formation were all inhibited by PN7051 at IC50 values between 0.3 and 0.7 mM. The cyclic peptide is proposed to affect FVII/TF/FX complex formation and function. The therapeutic profile of this molecule thus offers hope for improved anti-coagulation strategies and it's further development is eagerly awaited.

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