Studies on antiulcer agents. III. Plausible mechanism of antisecretory action of ethyl 2[(1H-benzimadazol-2-yl)sulfinylmethyl]-4-dimethylamino- 5-pyrimidinecarboxylate, an H+/K(+)-ATPase inhibitor, based on its reaction with thiols.
To explore the mechanism of the gastric antisecretion activity of ethyl 2-[(1H-benzimidazol-2-yl)sulfinylmethyl]- 4-dimethylamino-5-pyrimidinecarboxylate (5), a potential H+/K(+)-ATPase inhibitor, in the acid compartment of parietal cells, its reaction with some alkylthiols in the presence of hydrochloric acid was investigated. Upon treatment with 2-mercaptoethanol under acidic conditions, 5 gave a characteristic 1:2 adduct, ethyl 4-[2-(2-hydroxyethyldithio)- 1-(2-hydroxyethylthio)ethylidenamino]pyrimido[1,2-a]benzimid azole-3- carboxylate (6), instead of providing a disulfide of type 3, 2-(2-alkyldithiomethylpyridino)benzimidazolide, the product predicted to be formed according to the reaction mechanism of common H+/K(+)-ATPase inhibitors, such as omeprazole or lansoprazole, with mercaptans. With a large excess of 2-mercaptoethanol, 5 provided 2-(2-hydroxyethylthio)-1H-benzimidazole (8) and ethyl 4-dimethylamino-2-(2-hydroxyethyldithio)-5-pyrimidinecarboxylat e (9) as well as 6. The transformation mechanisms and their implications are discussed.
Terashima
K
K
Research Laboratories, Roussel Morishita Co., Ltd., Shiga, Japan.
Muraoka
O
O
Ono
M
M
D000897:Anti-Ulcer Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D005750:Gastric Juice / Q000187:drug effects / Q000378:metabolism; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006851:Hydrochloric Acid / Q000378:metabolism; D008956:Models, Chemical; D054328:Proton Pump Inhibitors; D013329:Structure-Activity Relationship
D000897:Anti-Ulcer Agents; D001562:Benzimidazoles; D054328:Proton Pump Inhibitors; C092689:ethyl 2-((1H-benzimidazol-2-yl)sulfinylmethyl)-4-dimethylamino-5-pyrimidinecarboxylate; D006851:Hydrochloric Acid