1998 年 118 巻 3 号 p. 88-104
A series of the aryl-substituted N'-2-(2-hydroxy-2-phenyl) ethyl derivatives of N"-methanesulfonyl-N-2-((5-dimethylaminomethyl or 5-methylaminomethyl)furfurylthio)ethylguanidine have been synthesized as potential antisecretory and mucosal protective antiulcer agents. The synthetic routes involves, at the last stage, the reaction of 2-hydroxy-2-phenylethylamines with N-2-(furfurylthio)-ethyl-N'-methanesulfonyl-S-methylisothiourea or its O-phenylisourea counterpart. The primary screening test to assess the inhibitory activity of the synthetic compounds on histamine-induced gastric acid secretion was carried out in anesthetized rats by the lumen-perfusion technique of Ghosh and Schild and also by the pylorus-ligated preparation method. The best profile of histamine H2-antagonist activity was much better than that of the prototype ranitidine, and obtained with N'-(2-(2-hydroxy-2-(4-hydroxyphenyl))ethyl-N"-methanesulfonyl-N-2-(5-(methylaminomethyl)furfurylthio)ethylguanidine (12f), which was also characterized by enhancing the gastric mucosal blood flow in rabbits as observed by the thermoelectric method. This compound 12f, designated as T-593, significantly inhibited the formation of the indomethacin-induced gastric lesions in rats ; 3.5-fold more potent than ranitidine, but 4-fold less active than famotidine. On the other hand, T-593 and famotidine displayed comparable activities in healing the acetic acid-induced gastric ulcer with and without the dosing of indomethacin. Additional notable features of T-593, as determined in rats, are that its protective effect on the hemorrhagic shock-induced lesion under the prior dosing of histamine is ca. 10-and 2-fold greater than ranitidine and famotidine, respectively, and that a decrease in the gastric mucosal blood flow caused by a partial blood-withdrawal is more strongly recovered with T-593 than with famotidine. These experimental results suggest that the antiulcer efficacy of T-593 can be explained by its dual activities : antisecretion of gastric acid and, more importantly, protection of gastric mucous membrane.