Studies on Antiulcer Agents. III. Plausible Mechanism of Antisecretory Action of Ethyl 2-[(lH-Benzimidazol-2-yl)sulfinylmethyl]-4-dimethylamino-5-pyrimidinecarboxylate, an H+/K+-ATPase Inhibitor, Based on Its Reaction with Thiols

Abstract

To explore the mechanism of the gastric antisecretion activity of ethyl 2-[(lH-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)-l-(2-hydroxyethylthio)ethylidenamino]pyrimido[l,2-a]benzimidazole-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)-lH-benzimidazole (8) and ethyl 4-dimethylamino-2-(2-hydroxyethyldithio)-5-pyrimidinecarboxylate (9) as well as 6. The transformation mechanisms and their implications are discussed. © 1995, The Pharmaceutical Society of Japan. All rights reserved.