Development of potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity relationship.

Based on structure-activity relationship studies, we designed and synthesized plasmin (PL) and plasma kallikrein (PK) inhibitors. Trans-(4-aminomethylcyclohexanecarbonyl)-Tyr(O-Pic)-octylamide inhibited PL, PK, urokinase (UK) and thrombin (TH) with IC50 values of 0.53, 30, 5.3 and > 400 microm, respectively. Trans-(4-aminomethylcyclohexanecarbonyl)-Tyr(O-2-Pyrim)-4-carboxyanilide inhibited PL, PK, UK and TH with IC50 values of 36, 0.56, 440 and > 1,000 microM, respectively.