Synthetic low-molecular weight thrombin inhibitors: molecular design and pharmacological profile

Thrombin is a multifunctional protein: in addition to its role in coagulation, thrombin has important biological effects on platelets, endothelial and smooth muscle cells, leukocytes, the heart and neurones. A detailed understanding of the structure of thrombin, of related serine proteases and of enzyme-inhibitor complexes has aided in the discovery of potent and selective new inhibitor molecules. Some of these novel thrombin inhibitors are active when administered orally and have shown remarkable efficacy as antithrombotic agents in animal models, offering a greater therapeutic potential than presently available drugs. This potential extends also to non-thrombotic indications where thrombin may be involved, namely inflammation, cancer and neurodegenerative diseases. The recent identification of specific thrombin receptors on different cells provides an alternative strategy for inhibiting thrombin's cellular actions, without necessarily compromising its role in haemostasis. In this review, Carlo Tapparelli and colleagues present a comprehensive update of these recent developments in the field of thrombin biology and pharmacology suggesting a new era of therapeutic drugs is on the horizon.