Structure-activity relationships of inhibitors derived from 3-amidinophenylalanine.

Thrombin is the key enzyme in coagulation and its inhibitors are of therapeutic interest since they are potential anticoagulants. The most potent inhibitor of the benzamidine type is N alpha-(2-naphthylsulfonyl-glycyl)-4-amidinophenylalanine piperidide (NAPAP). However, NAPAP and other substances designed so far do not fulfill the pharmacological requirements. The goal of designing new compounds was to obtain potent inhibitors with improved pharmacokinetic properties, such as absorption after oral application and a sustained elimination. Novel derivatives of 3-amidinophenylalanine as key building block were synthesized. The amidino moiety and both the N alpha- and the C-terminal substituents were widely varied. Some of the newly synthesized compounds are potent inhibitors of thrombin and exert improved pharmacokinetic properties.