Pharmacological properties of the gastric H(+)/K(+) ATPase inhibitor, AU-461

AU-461 (1-(2-methyl-4-methoxyphenyl)-4-(2-hydroxyethyl)amino]-6-beta,beta, beta-trifluoroethoxy-2,3-dihydropyrrolo3,2-c]quinoline) was tested for its ability to act as an anti-ulcer agent. AU-461 inhibited gastric H(+)/K(+) ATPase activities with IC(50) values of 12.15 and 4.20 micromol/l for rabbit and pig enzymes, respectively. The inhibition was reversible, and competitive with respect to the activating cation K(+). When AU-461 was examined for the in vivo antisecretory activity, we found that AU-461 reduced the histamine-stimulated acid secretion as well as the basal secretion in rat stomach. Duration of the antisecretory effect was about 6 h upon oral administration. AU-461 prevented dose-dependently the ulcer formation produced by either ethanol or NaOH. This protective effect was not altered by indomethacin pretreatment. In addition, the elevated plasma gastrin by the oral administration of AU-461 was returned to control by 12 h. Taken together, these results suggest that AU-461 could be developed as a new therapeutic agent for peptic ulcer disease.