Synthesis of trans-4-Aminomethylcyclohexanecarbonyl-L- and -D-phenylalanine-4-carboxymethylanilide and Examination of Their Inhibitory Activity against Plasma Kallikrein

Abstract

Based on studies of structure-activity relationship, trans-4-aminomethylcyclohexanecarbonyl-L-phenylalanine-4-carboxymethylanilide (Tra-Phe-APAA) was designed as a selective plasma kallikrein inhibitor and synthesized. Tra-Phe-APAA inhibited plasma kallikrein with a K_i value of 0.81 μM, while it inhibited glandular kallikrein, plasmin, urokinase, factor Xa and thrombin with K_i values of >500, 390, 200, >500, and >500 μM, respectively. However, its stereoisomer, Tra-D-Phe-APPA did not exhibit any detectable inhibitory activity against the above enzymes.