Progress towards the discovery of orally active thrombin inhibitors.

The serine protease thrombin is a key enzyme in the control of blood coagulation and displays numerous other effects on platelet, endothelial and smooth muscle cell function. The pre-eminence of thrombin in the coagulation cascade has made the enzyme a popular drug target in the search for more clinically acceptable and safe anti-coagulants. This concept has been particularly strengthened by the demonstration that direct inhibitors of thrombin such as Revasc are clinically effective. A number of low molecular weight thrombin inhibitors have now been described in the literature although to date because of their inherent low bioavailability compounds have been limited to the parenteral route of administration. The introduction of appropriate pharmacokinetic properties into these first generation thrombin inhibitors has been problematic despite intensive research in this area. However, the first pre clinical examples of direct thrombin inhibitors possessing good oral bioavailability is now emerging. This review updates current developments in the progress towards the discovery of orally available thrombin inhibitors and suggests that the first clinical validation of drugs from this field is imminent.