Chapter 8. Antithrombotics/Serine Proteases

Publisher Summary Anti-coagulants, particularly bifunctional inhibitors of thrombin and more recently small, naturally occurring protein inhibitors of factor Vlla and Xa, continue to be investigated as possible acute agents. The use of anti-coagulants in the treatment and prevention of both acute and chronic thrombosis-related disorders is growing at a rapid pace in part because of an increasing geriatric population and the recognition of intravascular clot formation, as a causative factor, in a number of important cardiovascular diseases, such as myocardial infarction, unstable angina, deep vein thrombosis, pulmonary embolism, and ischemic stroke. The mechanism of all current anti-coagulant strategies is the inhibition of one or more of the trypsin-like serine proteases that catalyze blood coagulation through the sequential amplified activation of the corresponding zymogens for these enzymes. Till date there are only two anti-coagulant strategies in the treatment of acute and chronic thrombosis; heparin and related derivatives and vitamin K antagonists. The limitations of both the heparins and vitamin K antagonists have stimulated the search for new therapeutic alternatives based on the selective inhibition of the principle serine proteases catalyzing thrombus formation. This has been aided by the determination of the three dimensional crystal structures of virtually all of the key enzymes in the blood coagulation cascade that has helped in the design of synthetic compounds that specifically block enzymatic activity. Additionally, the use of exquisitely selective natural inhibitors derived from blood feeding organisms has also provided key insight into the pharmacological effects of selective inhibition of the coagulation serine proteases at different levels in this cascade. This chapter discusses the recent developments in the search for such new generation of synthetic anti-coagulants with some discussion on the use of natural anti-coagulants to gain further insight into the inhibitor design and pharmacological efficacy.