SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF POTENT THROMBIN INHIBITORS - PIPERAZIDES OF 3-AMIDINOPHENYLALANINE

Thrombin is the key enzyme in the blood coagulation system, and inhibi tors of its proteolytic activity are of therapeutic interest since the y are potential anticoagulants. The most potent inhibitor of the benza midine type is ylsulfonyl)glycyl]-4-amidinophenylalanylpiperidide (NAP AP). However, NAPAP and other benzamidine derivatives do not show favo rable pharmacological properties; above all, they have very low system ic bioavailability after oral administration. The goal of designing ne w compounds was to obtain potent inhibitors with improved pharmacokine tic properties. Piperazide derivatives of 3-amidinophenylalanine as th e key building block were synthesized. The piperazine moiety opened th e possibility to introduce quite different substituents on the second nitrogen using common synthetic procedures. Some of the newly synthesi zed compounds are potent inhibitors of thrombin and offer an approach to study structure-function relationships for inhibition of thrombin a nd related enzymes and for the improvement of their pharmacokinetic pr operties.