INHIBITION OF GASTRIC-ACID SECRETION BY 1,8-NAPHTHYRIDIN-2(1H)-ONES

A number of 1-[(dialkylamino)alkyl]-1, 8-naphthyridin-2(1H)-ones were prepared and evaluated in vivo for inhibition of gastric acid secretion evoked by gastrin tetrapeptide and also in vitro for antagonism of the rat uterine histamine H2 receptor. The effect on activity of structural variation in the dialkylaminoalkyl group and the position and nature of naphthyridine ring substituents was examined. In this series, structural requirements for in vitro activity were found to be quite different from those required for maximal in vivo potency, and a positive correlation between histamine H2-receptor antagonism and inhibition of gastrin tetrapeptide induced secretion could not be established. In addition, none of the compounds inhibited histamine-stimulated gastric secretion. 1-[2-(Dimethylamino)-ethyl]-1, 8-naphthyridin-2(1H)-one and its 5-and 6-methyl analogues were the most potent in vivo inhibitors of gastrin tetrapeptide induced acid secretion, causing a 55-60% decrease in acid concentration at an oral dose of 20 mg/kg. However, they were only weakly active in vitro. On the other hand, 7-alkyl analogues, such as those with a 7-ethyl, 7-isopropyl, or 7-isobutyl substituent, had low in vivo potency but were excellent inhibitors, equivalent to metiamide, in the H2-receptor assay. © 1979, American Chemical Society. All rights reserved.