Potent antibacterial activity of Y-754, a novel benzimidazole compound with selective action against Helicobacter pylori.

Y-754, a novel benzimidazole compound, was investigated for in vitro and in vivo antibacterial activity. Unlike amoxicillin, clarithromycin, and metronidazole, the compound had no activity against common aerobic and anaerobic bacteria other than Helicobacter pylori. The minimum inhibitory concentration of Y-754 against H. pylori, at 0.025 microg/ml, was nearly equal to that of amoxicillin and clarithromycin. The respective concentrations of Y-754, amoxicillin, clarithromycin, and metronidazole required to inhibit 90% of 39 isolates of H. pylori were 0.05, 0.39, 6.25, and 25 microg/ml, indicating the potent activity of Y-754, including activity against clarithromycin- and metronidazole-resistant strains. The anti-H. pylori activity of Y-754 was potent even at pH 5.5 and was bactericidal at concentrations of 0.1 microg/ml and above. Exposure of H. pylori to Y-754 did not result in the induction of drug-resistant mutation. Oral administration (10 mg/kg twice a day for 7 days) to Mongolian gerbils infected with strain ATCC 43504 demonstrated that Y-754 was effective in H. pylori eradication and that its eradication efficacy increased in line with the progress of damage to the gastric mucosa caused by H. pylori infection. Y-754 was also efficacious in the treatment of infection by the clarithromycin-resistant strain OIT-36. The results obtained lead to the expectation that the new benzimidazole Y-754 will, in the near future, be used for H. pylori eradication therapy in peptic ulcer patients.

Design and synthesis of orally active benzamide derivatives as potent serotonin 4 receptor agonist.

A series of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide derivatives bearing an aralkylamino, alkylamino, benzoyl or phenylsulfonyl group at its side chain part at the 1-position on the piperidine ring was synthesized. They were evaluated for serotonin 4 (5-HT(4)) receptor agonist activity by testing their ability to contract the isolated guinea-pig ascending colon. 4-Amino-5-chloro-2-methoxy-N-[1-[5-(1-methylindol-3-ylcarbonylamino)pentyl]piperidin-4-ylmethyl]benzamide (1a, Y-34959) and its related compounds possessed favorable pharmacological profiles for gastrointestinal motility. Unfortunately, the compound 1a showed low bioavailability when given orally presumably due to its poor intestinal absorption rate. Replacement of the 1-methylindol-3-yl carbonylamino moiety of 1a with an aralkylamino (or alkylamino) group did not improve the intestinal absorption rate. Replacement of the 1-methylindol-3-ylcarbonylamino moiety with a benzoyl or phenylsulfonyl group increased the intestinal absorption rate compared with 1a. These compounds revealed good pharmacological profiles for gastrointestinal motility and were superior to 1a in oral bioavailability.

In vitro and in vivo anti- Helicobacter pylori activity of Y-904, a new fluoroquinolone.

Y-904 is a new fluoroquinolone with a broad antimicrobial spectrum. In particular, it has anti- Helicobacter pylori activity superior to that of existing fluoroquinolones. In the present study it was examined for its in vitro antibacterial activity against 51 clinical isolates of H. pylori, including clarithromycin- and metronidazole-resistant strains. The minimum inhibitory concentration of Y-904 at which 90% of isolates were inhibited was close to that of amoxicillin and clarithromycin and lower than that of levofloxacin and metronidazole (0.1, 0.1, 0.2, 3.13, and 12.5 micrograms/ml, respectively). Y-904 showed equally strong activity at pH 5.5 as at pH 7.0. At 10 times the minimum inhibitory concentration, Y-904 decreased the viable count of H. pylori to below 10(-5) within 2 h after exposure. No significant change in the minimum inhibitory concentration was observed when H. pylori, Staphylococcus aureus, and Escherichia coli were successively subcultured in medium containing subinhibitory concentrations of Y-904. Y-904 also strongly inhibited the supercoiling activity of DNA gyrase from H. pylori ATCC43504 (IC(50), 1.48 micrograms/ml). A study of Y-904 treatment in H. pylori-infected Mongolian gerbils using twice-daily oral administration for 7 days demonstrated that the complete clearance dose of Y-904 was 1 mg/kg and that its potency was around 10, 30, and 30 times that of amoxicillin, clarithromycin, and levofloxacin, respectively. These results indicate that Y-904 is a promising candidate for the eradication of H. pylori infection.

Long-term effects of Helicobacter pylori eradication in Mongolian gerbils.

BACKGROUND: In this study, to clarify whether Helicobacter pylori eradication alters the course of the development of gastric mucosal changes in the stomach, we examined the long-term effects of H. pylori eradication on H. pylori-inoculated gerbils. METHODS: A total of 40 H. pylori-inoculated gerbils were randomized and subjected, at 22 months after inoculation, to eradication treatment with dual therapy of omeprazole plus clarithromycin, or with therapy with a novel quinolone compound, Y-34867, alone. The animals were killed at the start of administration (control group) or at 8 months after the completion of therapy (vehicle or eradication-treatment groups). RESULTS: Severe histopathological changes in the gastric mucosa were observed in all H. pylori-inoculated gerbils at the start of administration. At 8 months after completion of therapy, the frequency of gastritis, erosion, intestinal metaplasia, and gastric carcinoid in the eradication therapy groups was markedly reduced compared with that in the control and vehicle groups. Values for anti- H. pylori IgG titer, bacterial counts, and gastrin also decreased significantly. CONCLUSIONS: These results suggest that H. pylori eradication may have had a therapeutic effect not only on gastritis, erosion, and gastric ulcer but also on glandular atrophy, intestinal metaplasia, and gastric carcinoid.