PROGRESS TOWARDS THE DISCOVERY OF ORALLY-ACTIVE THROMBIN INHIBITORS

The serine protease thrombin is a key enzyme in the control of blood c oagulation and displays numerous other effects on platelet, endothelia l 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 c oncept has been particularly strengthened by the demonstration that di rect inhibitors of thrombin such as Revasc(TM) are clinically effectiv e. 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 parentral rout e of administration. The introduction of appropriate pharmacokinetic p roperties into these first generation thrombin inhibitors has been pro blematic despite intensive research in this area. However, the first p re clinical examples of direct thrombin inhibitors possessing good ora l bioavai[ability is now emerging. This review updates current develop ments in the progress towards the discovery of orally available thromb in inhibitors and suggests that the first clinical validation of drugs from this field is imminent.