Biochemical and pharmacological properties of a newly synthesized proton pump (H+/K(+)-ATPase) inhibitor, TY-11345 in experimental animals.
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.
Yamaguchi
T
T
R & D Department, Toa Eiyo Ltd., Fukushima, Japan.
Aihara
K
K
Yamada
S
S
Narita
S
S
Kogi
K
K
D000085:Acetates; D019342:Acetic Acid; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D004381:Duodenal Ulcer / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D004840:Epirizole; D000431:Ethanol; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007101:Immersion; D066298:In Vitro Techniques; D007213:Indomethacin; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009853:Omeprazole / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D013315:Stress, Psychological / Q000503:physiopathology; D013758:Tetragastrin / Q000494:pharmacology
D000085:Acetates; D000897:Anti-Ulcer Agents; D001562:Benzimidazoles; D054328:Proton Pump Inhibitors; D013758:Tetragastrin; C084138:TY 11345; D004840:Epirizole; D000431:Ethanol; D009853:Omeprazole; D019342:Acetic Acid; D007213:Indomethacin