Pharmacokinetic Properties of a Novel Gastric Proton Pump Inhibitor, (±)-2-[(4-Methoxy-6,7,8,9-Tetrahydro-5h-Cyclohepta[d]Pyridin-9-yl) Sulfinyl]-1h-Benzimidazole Sodium Salt, in Healthy Subjects

Q3 · MEDICINE

Article

Author: Akira Sato ; Toshihiko Uematsu ; Mitsuyoshi Nakashima ; Akihiko Nagai ; Kazuhiro Kosuge ; Masako Nakano

The pharmacokinetics and safety of TY-11345 [(+/-)-2-[(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9- yl)sulfinyl]-1H-benzimidazole sodium salt], a novel gastric proton pump inhibitor, were studied in healthy male volunteers after single (20, 40, and 80 mg) and repeated oral doses (60 mg, once daily for 7 days) as enteric-coated tablet. At the single doses of 20 and 40 mg, intragastric pH was continuously monitored in each of two subjects. No abnormal findings definitely attributable to the test drug were observed throughout the study. In the single-dose study, the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve of TY-11345 increased in a dose-proportional manner. The time to reach Cmax was about 3 h after dosing and plasma concentrations declined thereafter with a half-life of about 1 h irrespective of dose. The effect of food intake on the pharmacokinetic parameters of TY-11345, which was evaluated at the dose of 40 mg in a cross-over design, was not significant. TY-11345 was not detected in urine unchanged, while a main metabolite and its conjugate were identified in urine as 32-38% of the dose. An intragastric pH value over 4 was obtained about 3 h after the administration of 40 mg and maintained for more than 5 h, despite the fall of plasma concentration. This effect was less obvious at a dose of 20 mg. In the multiple-dose study, the pharmacokinetics exhibited no substantial difference between the first and last doses.(ABSTRACT TRUNCATED AT 250 WORDS)

01 Jan 1994·Chemical and Pharmaceutical BulletinQ4 · MEDICINE

Syntheses and Antiulcer Activities of Novel 2-((6,7,8,9-Tetrahydro-5H-cyclohepta(b)pyridin-9-yl)sulfin-yl)-1H-benzimidazole Analogues.

Q4 · MEDICINE

Article

Author: Narita, Sen-ichi ; Goto, Takao ; Yamada, Shin-ichi ; Shimanuki, Eiji

A synthetic study on a series of benzimidazole derivatives including cycloalka[b]pyridine moiety has been carried out. Among these compounds synthesized, a novel antipeptic agent with 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine moiety (TY-11345) was found to be superior to omeprazole in (H+ + K+)-ATPase inhibitory activity and antisecretory potencies.

01 Jan 1993·Japanese Journal of Pharmacology

Pharmacological Analysis of Receptors Involved in the Late, Tachykininergic Contractile Response to Electrical Transmural Stimulation in Isolated Rabbit Iris Sphincter Muscle

Article

Author: Sen-ichi Narita ; Kentaro Kogi ; Takaji Yamaguchi ; Kazuyuki Aihara ; Shin-ichi Yamada

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Peptic Ulcer	Phase 2	JP	TOA Eiyo Ltd.	-
Stomach Ulcer	Phase 2	-	TOA Eiyo Ltd.	-

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