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

• Published in: Japanese journal of pharmacology Vol. 35; no. 3; pp. 203 - 227
• Main Authors: AOYAMA, Takuo, INO, Yoshitaka, OZEKI, Masayuki, ODA, Minoru, SATO, Takuo, KOSHIYAMA, Yoshiko, SUZUKI, Shoshi, FUJITA, Mitsunobu
• Format: Journal Article
• Language: English
• Published: Kyoto The Japanese Pharmacological Society 01.07.1984; Japanese Pharmacological Society
• Subjects: Animals; Anti-Inflammatory Agents; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Complement Activation - drug effects; Complement Inactivator Proteins - pharmacology; Forssman Antigen - analysis; Guanidines - pharmacology; Guinea Pigs; Hemolysis - drug effects; In Vitro Techniques; Inflammation - metabolism; Kinins - biosynthesis; Kinins - metabolism; Lipase - antagonists & inhibitors; Male; Medical sciences; Mice; Pharmacology. Drug treatments; Phospholipases A - antagonists & inhibitors; Protease Inhibitors - pharmacology; Rabbits; Rats; Shock, Septic - prevention & control; Shwartzman Phenomenon - prevention & control; Thrombin - antagonists & inhibitors; Trypsin Inhibitors - pharmacology; Animal model; Trypsin; Proteinase; Enzyme inhibitor; Thrombin; Complement; Biological activity
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1254/jjp.35.203

FUT-175, 6-amidino-2-naphthyl p-guanidinobenzoate dimethanesul-fonate (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.