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

Abstract

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 Kj values were 0.048 ,uM, 0.18 flM, 0.29 jiM, 0.31 uM, 3.6 ,uM and 47 jiM, respectively. In addition, ONO-3307 inhibited both elastase release from N-formyl-Met-I-eu-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 de veloped 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 treat ment of protease-mediated diseases such as thrombosis and DIC.

Recent Advances on Plasmin Inhibitors for the Treatment of Fibrinolysis‐Related Disorders

“…) are guanidine/amidine‐based, highly nonselective serine proteases inhibitors. The first two molecules inhibit plasmin with a K i of 0.31 μM, whereas 47 inhibits with sixfold lower potency . They also inhibit trypsin, thrombin, and kallikrein competitively ( K i < 5 μM) and their effects can be reversed by dialysis .…”

“…In addition, 100 μM ONO‐3307 was shown to inhibit elastase release from stimulated human leukocytes. Likewise, the three inhibitors inhibited thromboplastin release from stimulated leukocytes at ∼10 μM dosage . Due to the combined effect on thrombin (coagulation) and plasmin (fibrinolysis), ONO‐3307 was tested as a treatment for DIC and pancreatitis .…”

“…136 They also inhibit trypsin, thrombin, and kallikrein competitively (K i < 5 μM) and their effects can be reversed by dialysis. 136 ONO-3307 and gabexate were shown to completely inhibit the deposition of labeled fibrinogen in kidney, lung, and liver in experimental animal model of t-AMCHA-induced thrombosis in rats at 10 mg/kg/hr. In addition, 100 μM ONO-3307 was shown to inhibit elastase release from stimulated human leukocytes.…”

Protection by a New Synthetic Protease Inhibitor, ONO3307, of the Rat Exocrine Pancreas during Acute Edematous Pancreatitis Induced by a Supramaximal Dose of Caerulein in Comparison with FOY007

“…ONO3307 has been reported to be more potent than FOY007 [16], The relatively lowmolecular weights of ONO3307 (430 daltons) and FOY007 (418 daltons) suggest that they migth penetrate into pancreatic acinar cells from the vasculature and have encouraged studies to evaluate their ability to protect against pancreatitis at both the cellular and the subcellular levels. Their clinical use in the treatment of acute pancreatitis is also to be considered.…”

“…In this communication, we describe the effects of the new potent low-molecularweight protease inhibitor ONO3307 in caerulein-induced pancreatitis, which has been re ported to be a most potent serine protease inhibitor [16], and to have some inhibitory effects on inflammatory cells from the several parameters including in vitro cellular and subcellular organelle fragility. In addition, a comparison ONO3307 and FOY007 (gabexate mesilate), which has been used clinically in Japan was performed.…”