TAFIa inhibitors in the treatment of thrombosis.

Since activated thrombin-activatable fibrinolysis inhibitor (TAFIa) was discovered in 1988, considerable interest has developed in the biological role of this enzyme, particularly in hemostasis and thrombotic diseases. Given the large number of publications about the underpinning biology of fibrinolysis, the relatively small number of reported chemical tools or drug-like molecules that target this mechanism is surprising. In the context of drug design, most of the disclosed fibrinolysis inhibitors occupy less-exploited regions of drug-like space. To generalize, most of these molecules are either small and hydrophilic, or are larger carboxylic acids. The chemical nature of these inhibitors reflects those of the endogenous substrate for this zinc metalloprotease enzyme target. Knowledge of the target has defined the way medicinal chemists have designed inhibitors to target this enzyme of intriguing therapeutic potential. This review summarizes the publications, patent literature and company disclosures on small-molecule inhibitors of TAFIa from 2006 to the present. Selected significant disclosures prior to this period are also highlighted.