[19] Synthetic selective inhibitors of thrombin

Publisher Summary In circulatory blood, thrombin is found as the zymogen, prothrombin, which is activated by intrinsic and extrinsic pathways. Once activated, thrombin is neutralized by plasma antithrombins, e.g., antithrombin III (ATIII). The result is that active thrombin is rarely found in circulatory blood. However, the activation of thrombin occurs in pathological states and such activation is undoubtedly hazardous. The synthetic selective inhibitors discussed in this chapter are designed based on biochemical knowledge regarding the conversion of fibrinogen by thrombin to fibrin. Studies on the fibrinopeptides described in the chapter suggests that thrombin recognizes the L-arginine residue, in particular its biophysical and geometrical arrangements. Therefore, L-arginine is the most promising skeleton for designing thrombin inhibitors for studying the structure–function relationship between a number of arginine derivatives and their thrombin inhibitory activity. It is known that (1) argatroban accelerates fibrinolysis by t-PA, (2) argatroban inhibits the activation of FXIII, (3) argatroban may inhibit the activity of the remaining thrombin within the thrombi, and (4) argatroban does not require ATIII.