Biochemical and pharmacological properties of a newly synthesized proton pump (H+/K(+)-ATPase) inhibitor, TY-11345 in experimental animals.

Abstract

We investigated the effects of the newly synthesized proton pump inhibitor TY-11345, (+/-)-2-[(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin- 9-yl)sulfinyl]-1H-benzimidazole sodium salt, on gastric mucosal proton pump (H+/K(+)-ATPase) activity, gastric acid secretion and gastro-duodenal lesions in experimental animals. TY-11345 potently inhibited H+/K(+)-ATPase activity in isolated rabbit gastric mucosal microsomes; and the inhibitory effect was enhanced under weak acid conditions, the IC50 (concentrations that inhibit the enzyme activity by 50%) being 5.8 microM and 9.9 microM at pH 6.0 and pH 7.4, respectively. In Ghosh & Schild rats, intravenous injection of TY-11345 significantly inhibited gastric acid secretion stimulated by tetragastrin; the effect of TY-11345 was twice as potent as that of omeprazole. In pylorus ligated rats, TY-11345 inhibited basal gastric acid secretion by both the intraduodenal and oral routes, with ED50 values of 1.2 and 4.0 mg/kg, respectively. These effects were 9 and 5 times more potent than those of omeprazole, respectively. Moreover, the antisecretory effect of TY-11345 persisted for more than 24 hr in pylorus ligated rats. In experimental ulcer models, TY-11345 prevented the formation of water-immersion stress, ethanol or indomethacin-induced gastric lesions and mepirizole-induced duodenal lesions in rats. The antiulcer effects of TY-11345 were 3 to 15 times more potent than those of omeprazole. These results suggest that TY-11345 has potent antisecretory and antiulcer effects which are exerted by suppression of H+/K(+)-ATPase activity in gastric parietal cells, so that TY-11345 should be useful for the clinical treatment of peptic ulcer diseases.

• Authors: T Yamaguchi, K Aihara, S Yamada, S Narita, K Kogi
• Journal: Japanese journal of pharmacology (Jpn J Pharmacol) Vol. 62 Issue 4 Pg. 363-71 (Aug 1993) ISSN: 0021-5198 [Print] Japan
• PMID: 8230863 (Publication Type: Journal Article)

Chemical References

• Acetates
• Anti-Ulcer Agents
• Benzimidazoles
• Proton Pump Inhibitors
• Tetragastrin
• TY 11345
• Epirizole
• Ethanol
• Omeprazole
• Acetic Acid
• Indomethacin

Topics

• Acetates
• Acetic Acid
• Animals
• Anti-Ulcer Agents (pharmacology)
• Benzimidazoles (pharmacology)
• Duodenal Ulcer (chemically induced, pathology, prevention & control)
• Epirizole
• Ethanol
• Gastric Mucosa (drug effects, enzymology, metabolism)
• Immersion
• In Vitro Techniques
• Indomethacin
• Male
• Microsomes (drug effects, enzymology, metabolism)
• Omeprazole (pharmacology)
• Proton Pump Inhibitors
• Rabbits
• Rats
• Rats, Sprague-Dawley
• Stomach Ulcer (chemically induced, pathology, prevention & control)
• Stress, Psychological (physiopathology)
• Tetragastrin (pharmacology)