Pharmacological Studies of FUT-175, Nafamstat Mesilate I. Inhibition of Protease Activity in in Vitro and in Vivo Experiments

Abstract
FUT-175, 6-amidino-2-naphthyl p-guanidinobenzoate dimethanesulfonate (nafamstat mesilate), a novel synthetic protease-inhibiting agent, was studied to determine its in vitro effects against various proteases and other enzymes, as well as to determine its in vivo protease inhibitory effects. FUT-175 inhibited in an intense, specific and reversible way, the enzyme activities of trypsin, C[complement component]1.hivin.r, C1.hivin.s, thrombin, kallikrein and plasmin with IC50 [median inhibitory concentration] values of the order of 10-6 to 10-8 M. FUT-175 also inhibited complement-mediated hemolysis, including both classical and alternative pathways, sites of inhibition being on C1.hivin.r and C1.hivin.s as evidenced by the intermediate-cell technique. In animal model reactions in which the complement system is known to be involved as pathogenetic factors, e.g., Forssman shock, Forssman cutaneous vasculitis, zymosan-induced paw edema, endotoxin shock and local Shwartzman reaction, FUT-175 was highly effective in that, for example, i.v. dosing at 3 mg/kg could completely protect guinea pigs from the lethal Forssman shock. FUT-175 was also effective in trypsin-induced shock in mice, in lethality due to thrombin-thrombosis in mice and in kinin formation in the inflammatory process in rats.