PHARMACOLOGICAL STUDIES OF FUT-175, NAFAMSTAT MESILATE .1. INHIBITION OF PROTEASE ACTIVITY IN INVITRO AND INVIVO EXPERIMENTS
PHARMACOLOGICAL STUDIES OF FUT-175, NAFAMSTAT MESILATE .1. INHIBITION OF PROTEASE ACTIVITY IN INVITRO AND INVIVO EXPERIMENTS
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DOI：
10.1254/jjp.35.203
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发表时间：
1984-01-01
期刊：
影响因子：
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通讯作者：
FUJITA, M
中科院分区：
文献类型：
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作者：
AOYAMA, T;INO, Y;FUJITA, M
FUT-175，6-脒基-2-萘基对胍基苯甲酸二甲磺酸盐（甲磺酸萘芬司他），一种新型的合成蛋白酶抑制剂，进行了研究，以确定其对各种蛋白酶和其他酶的体外作用，以及确定其体内蛋白酶抑制作用。FUT-175以强烈、特异性和可逆的方式抑制胰蛋白酶、C[补体成分]1.hivin.r、C1.hivin.s、凝血酶、激肽释放酶和纤溶酶的酶活性，IC 50 [中位抑制浓度]值约为10-6至10-8 M。FUT-175还抑制补体介导的溶血，包括经典和替代途径，抑制位点位于C1.hivin. r和C1.hivin. s，如中间细胞技术所证明。在已知补体系统作为致病因子参与的动物模型反应中，Forssman休克、Forssman皮肤血管炎、酵母多糖诱导的爪水肿、内毒素休克和局部Shwartzman反应，FUT-175高度有效，例如，静脉内给药3 mg/kg可完全保护豚鼠免受致死性Forssman休克。FUT-175在小鼠胰蛋白酶诱导的休克、小鼠凝血酶血栓形成导致的致死性和大鼠炎症过程中的激肽形成中也有效。
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.