Nicotinamide derivatives as a new class of gastric (H+/K+)-ATPase inhibitors. II. Synthesis and structure-activity relationships of 2-[(2,4- dimethoxyhenzyl)sulfinyl]-N-(4-pyridinyl)pyridine-3-carboxamides

Article abstract of DOI:10.1248/cpb.45.1027

Members of a new series of 2-[(2,4-dimethoxybenzyl)sulfinyl]-N-(4- pyridinyl)pyridine-3-carboxamides were synthesized and evaluated for their gastric antisecretory activity and the ability to inhibit cytochrome P450- dependent O-dealkylation of 7-ethoxycoumarin (7-EC) in rat liver microsomes. Several of the compounds synthesized exhibited potent inhibitory activities against both [¹⁴C]aminopyrine accumulation stimulated by dibutyryl cyclic AMP in isolated rabbit parietal cells and histamine-induced gastric acid secretion in pylorus-ligated rats when administered intraduodenally; their inhibitory activities were equivalent to or superior to those of the parent compound [2[(2,4-dimethoxybenzyl)sulfinyl]-N-(4-pyridinyl)pyridine-3- carboxamide] and omeprazole. Among the compounds having potent antisecretory activity in vitro and in vivo, 2-[(2,4-dimethoxybenzyl)sulfinyl]-N-(2,5- dimethyl-4-pyridinyl)pyridine-3-carboxamide and 2-[(2,4- dimethoxybenzyl)sulfinyl]-N-(2,6-dimethyl-4-pyridinyl)pyridine-3-carboxamide in particular showed lower inhibitory activity against the 7-EC deethylase than omeprazole. It seems probable that, unlike omeprazole, these compounds do not interact with a metabolism of other drugs in vivo. These compounds, therefore, are considered to be more promising candidate agents for treating acid-related gastrointestinal disorders than the parent compound reported previously.

Full text of DOI:10.1248/cpb.45.1027

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