Development of Active Center-Directed Plasmin and Plasma Kallikrein Inhibitors and Studies on the Structure-Inhibitory Activity Relationship

Abstract

The molecule of trans-4-aminomethylcyclohexanecarbonylphenylalanine 4-carboxymethylanilide (8), which is a potent and selective inhibitor of plasma kallikrein, can be devided into three parts (P₁, P_1' and P_2'), each of which contains one of the rings. In order to study the role of each part in the manifestation of potent and selective inhibitory activity and the relationship between the structure and inhibitory activities toward plasmin, plasma kallikrein, urokinase and thrombin, each part was substituted with various other moieties to give many kinds of analogs and their inhibitory activities against the above enzymes were examined. Among them, trans-4-aminomethylcyclohexanecarbonyl-O-2-bromobenzyloxycarbonyltyrosine 4-acetylanilide (12) inhibited plasmin and plasma kallikrein with IC₅₀ values of 2.3×10^-7 M and 3.7×10^-7 M, and K_i values of 1.2×10^-7 M and 1.3×10^-7 M, respectively.