Recent advances in the discovery of tissue factor/factor VIIa inhibitors and dual inhibitors of factor VIIa/factor Xa.

The search for an ideal anticoagulant has spanned decades and has taken several approaches to the identification of novel target molecules for preventing and treating thrombosis. In the group of anticoagulants acting through direct inhibition of coagulation factors, most research has focused on thrombin and factor Xa inhibitors. Attention has been drawn most recently to factor VIIa as a promising anticoagulation target, because of its role in complex with tissue factor, in initiating the coagulation cascade following blood vessel damage. Several reports suggest that inhibitors of the tissue factor/factor VIIa complex prevent thrombosis with a lower bleeding risk than other types of inhibitors. Accordingly, there is increasing interest in the generation of potent and selective small-molecule factor VIIa inhibitors that can be safely administered once or twice daily in an oral formulation with no need for routine coagulation monitoring. The emphasis of this review will be placed on recent advances in the development of the small-molecule inhibitors of factor VIIa complexed with tissue factor. The role of factor VIIa and tissue factor as initiators of the coagulation cascade following blood vessel damage is described, along with the structure of the active site of factor VIIa.