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A series of tripeptide derivatives was synthetizedand studied for blood clotting inhibition in vitro and in vivo experiments. Whole blood clotting time /WBCT/, activated partial thromboplastin time /APTT/, thrombin time /TT/ and prothrombin time /PT/ were measured in Thrombelastograph and Coagulometer, resp. using heparin and hirudin as reference substances. The inhibition by /1-4/ of platelet aggregation /PA/ was tested in Chrono-Log Aggregometer. The anticoagulant action of /1-4/ in vivo was investigated in mice, rats, rabbits, dogs and monkeys, resp. by different ways of administration. /1/ was found to be a non competitive inhibitor of thrombin according to Dixon plots /Ki = 7.5 × l0-8 M /. /1-4/ inhibited the thrombin induced PA specifically. By giving to animals i.v.,i.m.,s.c. and orally, resp. /1-4/ proved to be effective in all species and the anticoagulant action was dose dependent. In the course of continuous i.v.infusions to conscious rabbits and narcotized dogs, resp. /3-4 mg pro kg/hr for 3 to 6 hrs / WBCT, APTT and TT prolonged to 3-5 times of the starting values. The anticoagulant effect appeared 15 min after starting and returned to normal within 1-2 hrs after stop the infusions. No change either in blood pressure or in respiration could be observed during the infusions. ED50 and LD50 of i.v. infusion in conscious rabbits was found to be 1.3 and 58 mg, resp.. Our results suggest that /1-4/ represent powerful anticoagulant and antithrombotic effects and can be regarded as a new tyoe of anticoagulants.

thrombosis and haemostasis

Anticoagulant And Antithrombotic Properties Of D-PHE-PRO-ARG-H /1/, BOC-D-PHE-PRO-ARG-H /2/, BZ-D-ALE-PRO-ARG-H /3/ And β-D-Phenyl-Lactyl-PRO-ARG-H /4/