Inhibitory effects of ONO-3307 on various proteases and tissue thromboplastin in vitro and on experimental thrombosis in vivo.
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 Ki values were 0.048 microM, 0.18 microM, 0.29 microM, 0.31 microM, 3.6 microM and 47 microM, 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 diseases such as thrombosis and DIC.
Matsuoka
S
S
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
Futagami
M
M
Ohno
H
H
Imaki
K
K
Okegawa
T
T
Kawasaki
A
A
D000818:Animals; D001550:Benzamidines; D003956:Dialysis; D004731:Endotoxins / Q000494:pharmacology; D005343:Fibrinolytic Agents; D016670:Gabexate; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007700:Kinetics; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010196:Pancreatic Elastase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D015842:Serine Proteinase Inhibitors; D013925:Thromboplastin / Q000378:metabolism*
D001550:Benzamidines; D004731:Endotoxins; D005343:Fibrinolytic Agents; D006146:Guanidines; D007202:Indicators and Reagents; D015842:Serine Proteinase Inhibitors; D016670:Gabexate; D009240:N-Formylmethionine Leucyl-Phenylalanine; C062836:ONO 3307; D013925:Thromboplastin; D010196:Pancreatic Elastase; C032855:nafamostat