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CARDIOVASCULAR

Enhancement of Fibrinolysis by EF6265 [(S)-7-Amino-2-[[[(R)-2-methyl-1-(3-phenylpropanoylamino)propyl]hydroxyphosphinoyl] methyl]heptanoic Acid], a Specific Inhibitor of Plasma Carboxypeptidase B

Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama, Japan (K.S., Y.M., K.F., K.K., H.I., E.S., C.K., T.M., E.K., M.N., S.Y.); and Department of Public Health, Showa Pharmaceutical University, Machida, Tokyo, Japan (H.I.)

Plasma procarboxypeptidase B, also known as thrombin-activatable fibrinolysis inhibitor (TAFI), is converted by thrombin into the active enzyme, carboxypeptidase B (CPB)/activated TAFI. Plasma CPB down-regulates fibrinolysis by removing carboxy-terminal lysines, the ligands for plasminogen and tissue-type plasminogen activator (tPA), from partially degraded fibrin. To target thrombosis in a new way, we have identified and optimized a phosphinic acid-containing inhibitor of CPB, EF6265 [(S)-7-amino-2-[[[(R)-2-methyl-1-(3-phenylpropanoylamino) propyl]hydroxyphosphinoyl]methyl]heptanoic acid] and determined both the pharmacological profile and pathophysiological role of CPB in rat thrombolysis. EF6265 specifically inhibited plasma CPB activity with an IC₅₀ (50% inhibitory concentration) of 8.3 nM and enhanced tPA-mediated clot lysis in a concentration-dependent manner. EF6265 decreased detectable thrombi (percentage of glomerular fibrin deposition; control, 98 ± 1.1; EF6265, 0.1 mg/kg, 27 ± 9.1) that had been generated by tissue factor in a rat microthrombosis model with concomitant increases in plasma D-dimer concentration (control, <0.5 µg/ml; EF6265, 0.1 mg/kg, 15 ± 3.5 µg/ml). EF6265 reduced plasma 2-antiplasmin activity to a lesser extent than tPA. In an arteriovenous shunt model, EF6265 (1 mg/kg) enhanced exogenous tPA-mediated thrombolysis under the same conditions that neither EF6265 nor tPA (600 kIU/kg) alone reduced thrombi. EF6265 (1 and 30 mg/kg) did not affect the bleeding time in rats. Moreover, it did not prolong the bleeding time evoked by tPA (600 kIU/kg). These results confirm that circulating procarboxypeptidase B functions as a fibrinolysis inhibitor's zymogen and validates the use of CPB inhibitors as both an enhancer of physiological fibrinolysis in microcirculation and as a novel adjunctive agent to tPA for thromboembolic diseases while maintaining a small effect on primary hemostasis.

Address correspondence to: Dr. Kokichi Suzuki, R&D Planning, Meiji Seika Kaisha Ltd., 580 Horikawa-cho, Saiwai-ku, Kawasaki 212-0013, Japan. E-mail: kokichi_suzuki{at}meiji.co.jp