Open AccessPharmacological Studies of FUT-175, Nafamstat Mesilate I. Inhibition of Protease Activity in in Vitro and in Vivo Experiments
Author(s) -
Toshihiro Aoyama,
Yoshitaka Ino,
Masayuki Ozeki,
M. Oda,
Takuo Sato,
Yoshiko Koshiyama,
Sukeji Suzuki,
Mitsunobu Fujita
Publication year - 1984
Publication title -
japanese journal of pharmacology/japanese journal of pharmacology
Language(s) - English
Resource type - Journals
eISSN - 1347-3506
pISSN - 0021-5198
DOI - 10.1254/jjp.35.203
Subject(s) - proteases , in vivo , protease , chemistry , pharmacology , thrombin , in vitro , hemolysis , biochemistry , plasmin , enzyme , trypsin , immunology , platelet , biology , microbiology and biotechnology
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 was found to inhibit, in an intense, specific and reversible way, the enzyme activities of trypsin, C1r, C1s, thrombin, kallikrein and plasmin with IC50 values of the order of 10(-6)-10(-8) M. FUT-175 also inhibited complement-mediated hemolysis, including both classical and alternative pathways, sites of inhibition being on C1r and C1s 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, intravenous dosing at 3 mg/kg could completely protect guinea pigs from the lethal Forssman shock. FUT-175 was also found to be 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.