Peptide Boronic Acid Inhibitors of Thrombin

Abstract

Fibrin polymerization is the major component in venous thrombosis while both fibrin deposition and platelet aggregation are important in arterial thrombosis. Thrombin, the last protease in the blood coagulation cascade, hydrolyzes two bonds of fibrinogen to convert it into insoluble fibrin. Thrombin also catalyzes platelet aggregation. However, the predominance of thrombin catalysis in the latter reaction and in arterial thrombosis was not recognized until recently1. From earlier observations, it was known that the high molecular weight inhibitor, heparin-antithrombin III, was effective in blocking venous thrombosis, but was ineffective in blocking arterial thrombosis. This suggested that the thrombin catalyzed reaction was of limited importance in platelet aggregation. More recently, studies of Hanson and Harker1 demonstrated that the small peptide thrombin inhibitor, H-(D)Phe-Pro-ArgCH2C1, was highly effective in blocking arterial thrombosis in animal models. The differences in the behavior of the two thrombin inhibitors in blocking arterial thrombosis was attributed to the limited accessibility of the high molecular weight inhibitor to thrombin on the platelet surface. This result clearly suggests that the use of low molecular weight thrombin inhibitors in the control of arterial thrombosis will be advantageous.