Biochemical and Pharmacological Properties of a Newly Synthesized Proton Pump (H+/K+-ATPase) Inhibitor, TY-11345 in Experimental Animals.

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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]-]H-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 μM and 9.9 μM 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.

Biochemical and Pharmacological Properties of a Newly Synthesized Proton Pump (H+/K+-ATPase) Inhibitor, TY-11345 in Experimental Animals.

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