RESUMEN
A new series of 2-[(2-aminobenzyl, 4-aminobenzyl, and alpha-methylbenzyl) sulfinyl]-N-(4-pyridinyl)-3-pyridinecarboxamides. was synthesized and evaluated for gastric antisecretory activities. Several of the compounds synthesized exhibited potent inhibitory activities against [14C]aminopyrine accumulation stimulated by dibutyryl cyclic AMP in isolated rabbit parietal cells and histamine-induced gastric acid secretion in pylorus-ligated rats by intraduodenal administration. In particular, the more polar diastereoisomer of 2-[(4-methoxy-alpha-methylbenzyl)sulfinyl] -N-(4-pyridinyl)-3-pyridinecarboxamide (13b) showed in vivo inhibitory activity equivalent or superior to that of omeprazole and was a more selective (H+/K+)-ATPase inhibitor than omeprazole.
Asunto(s)
Antiácidos/síntesis química , Antiácidos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Niacinamida/análogos & derivados , Inhibidores de la Bomba de Protones , Animales , Ácido Gástrico/metabolismo , Masculino , Niacinamida/síntesis química , Niacinamida/farmacología , Células Parietales Gástricas/efectos de los fármacos , Células Parietales Gástricas/metabolismo , Piridinas/síntesis química , Piridinas/farmacología , Conejos , Ratas , Ratas Wistar , Tasa de Secreción/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Mucosa Gástrica/enzimología , Niacinamida/análogos & derivados , Inhibidores de la Bomba de Protones , Piridinas/química , 7-Alcoxicumarina O-Dealquilasa/antagonistas & inhibidores , Animales , Inhibidores Enzimáticos/farmacología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Histamina/farmacología , Masculino , Microsomas Hepáticos/enzimología , Modelos Químicos , Piridinas/farmacología , Conejos , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
A new series of N-Substituted 2-(benzhydryl- and benzylsulfinyl)nicotinamides 7 and 8 were synthesized. Upon acid activation in the acidic environment of the parietal cell, these compounds are converted into their active forms, 2,3-dihydro-3-oxoisothiazolo[5,4-b]pyridines 5, which inhibit gastric H+/K(+)-ATPase. Inhibitory activities against [14C]aminopyrine accumulation stimulated by dibutyryl cAMP in isolated rabbit parietal cells in vitro and histamine-induced gastric acid secretion in pylorus-ligated rats by intraduodenal administration in vivo were evaluated, and the structure-activity relationships were examined. Among the compounds synthesized, 2-[(2,4-dimethoxybenzyl)sulfinyl]-N-(4-pyridyl)nicotinamide (8b) showed potent inhibitory activities in vitro and in vivo equivalent to those of omeprazole, a typical H+/K(+)-ATPase inhibitor. Moreover, 8b was much more stable at neutral and weakly acidic pH than omeprazole, lansoprazole, and pantoprazole. Compound 8b is considered to be a promising agent for treating acid-related gastrointestinal disorders.