Nicotinamide derivatives as a new class of gastric (H+/K+)-ATPase inhibitors II. Synthesis and structure-activity relationships of 2[(2,4-dimethoxybenzyl)sulfinyl]-N-(4-pyridinyl)pyridine-3-carboxamides.
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.
Terauchi
H
H
Discovery Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Tanitame
A
A
Tada
K
K
Nakamura
K
K
Seto
Y
Y
Nishikawa
Y
Y
D015660:7-Alkoxycoumarin O-Dealkylase / Q000037:antagonists & inhibitors; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008956:Models, Chemical; D009536:Niacinamide / Q000031:analogs & derivatives*; D054328:Proton Pump Inhibitors; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D011725:Pyridines; D009536:Niacinamide; D006632:Histamine; D015660:7-Alkoxycoumarin O-Dealkylase