Pharmacological characterization of a new highly effective synthetic thrombin inhibitor

The most potent synthetic reversible thrombin inhibitor described so far, N alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide (Ki = 6 nmol/l), was studied with respect to its pharmacodynamics and pharmacokinetics in mice, rats and rabbits. In mice the LD50 was 54 mg/kg i.v. and greater than 800 mg/kg p.o. Prolongation of bleeding time in mice and reduction of mean arterial blood pressure in rats were seen only at doses above the antithrombotically effective doses. After i.v. injection in rabbits the plasma half-life was estimated to be about 9 min. Subcutaneous injection resulted in measurable inhibitor plasma levels for 4 h. Administration of high does into the duodenum did not give antithrombotically effective plasma levels. The ligature of the functional and nutritive hepatic vessels prolonged the half-life of the thrombin inhibitor, whereas renal excretion seems to be of minor importance. A dose-dependent antithrombotic effect was shown in venous stasis-induced thrombosis in rabbits.