Inhibitory effects of ONO-3307 on various proteases and tissue thromboplastin in vitro and on experimental thrombosis in vivo.

Abstract

The effect of ONO-3307 (4-sulfamoyl, phenyl-4-guanidinobenzoate methanesulfonate), a new protease inhibitor, was studied on various proteases in vitro and in an experimental thrombosis model in vivo. ONO-3307 competitively inhibited trypsin, thrombin, plasma kallikrein plasmin, pancreatic kallikrein and chymotrypsin; and their K1 values were 0.048 .mu.M, 0.18 .mu.M, 0.29 .mu.M, 0.31 .mu.M, 3.6 .mu.M and 47 .mu.M, respectively. In addition, ONO-3307 inhibited both elastase release from N-formyl-Met-Leu-Phe (fMLP)-stimulated leukocytes and tissue thromboplastin release from endotoxin-stimulated leukocytes. To examine the effects of ONO-3307 on disseminated intravascular coagulation (DIC), we developed an experimental thrombosis model. ONO-3307 (10 mg/kg/hr) completely inhibited the deposition of radioactive fibrin in kidney and lung. Gabexate mesilate (50 mg/kg/hr) was also effective in this model, but the effect of nafamostat mesilate was unclear. These results indicate that ONO-3307 exhibits a wide range of inhibitory effects on various proteases, and ONO-3307 may be useful for the treatment of protease-mediated diseses such as thrombosis and DIC.