STRUCTURE-ACTIVITY-RELATIONSHIPS OF INHIBITORS DERIVED FROM 3-AMIDINOPHENYLALANINE

Thrombin is the key enzyme in coagulation and its inhibitors are of th erapeutic interest since they are potential anticoagulants. The most p otent inhibitor of the benzamidine type is N -(2-naphthylsulfonylglycy l)-4-amidinophenylalanine piperidide (NAPAP). However, NAPAP and other substances designed so far do not fulfill the pharmacological require ments. The goal of designing new compounds was to obtain potent inhibi tors with improved pharmacokinetic properties, such as absorption afte r oral application and a sustained elimination. Novel derivatives of 3 -amidinophenylalanine as key building block were synthesized. The amid ino moiety and both the N alpha- and the C-terminal substituents were widely varied. Some of the newly synthesized compounds are potent inhi bitors of thrombin and exert improved pharmacokinetic properties.