• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.197-197
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• 1996

Helicobacter pylori (H. pylori) is a microaerophilic spiral bacterium and infection by it in the human stomach causes gastritis, furthermore, it is considered to be involved in the pathogenesis of peptic ulcers and the development of gastric carcinoma. We assessed the inhibitory activity of new antiulcer drugs against Helicobacter pylori. The activities of new antiulcer agents against Helicobacter pylori strains were determined by the standard agar dilution method with blood agar base #2, supplemented with 5% sheep blood and 4 antibiotics to support growth of these organisms. They were inoculated by multipoint inoculator and incubated at 37$^{\circ}C$ for 3 days under microaerophilic atmosphere. The MIC of antiulcer agents was the lowest concentration that inhibited visible growth of these organisms. According to results of various biochemical tests, these bacteria were identified as Helicobacter pylori strains. And the MIC results showed that the strains were very susceptible to omeprazole and YJA20379s. Some of YJA20379s were more potent than omeprazole. These results suggest that our new antiulcer drugs have potent inhibitory activity against Helicobacter pylori, so that our new antiulcer drugs might be useful for the clinical eradication of gastrointestinal Helicobacter pylori.

• YAKHAK HOEJI
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• v.35 no.5
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• pp.368-371
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• 1991

For the development of new antiulcer agents 5, 6-dihydroimidazo[2, 1-b]- thiazoles substituted at the 3-position are sythesized. Thus, the reaction of 3-chloromethyl-5, 6-dihydroimidazo[2, 1-b]thiazole(2) with thiourea and subsequently with 3-chloro-propionitrile gives 3-[3-[5, 6-dihydroimidazo[2, 1-b]thiazolyl]methylthio]propionitrile(4), which by partial alcoholysis with methanol is converted into methyl-3-[3-[5, 6-dihydro-imidazo[2, 1-b]thiazoyl]methylthio]propionimidate(5) . This compound(5) is treated finally with sulfamide or sulfonamides. 3-[3-[5, 6-dihydroimidazo[2, 1-b]thiazoyl]methylthiol-N$^{2}$-sulfamoyl-propionamidine(6) inhibited gastric acid secretion (45%) when administered intraduodenally (100 mg/kg) to pylorus-ligated rats.

• Archives of Pharmacal Research
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• v.16 no.2
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• pp.158-160
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• 1993

2-Oxazolidinones and 1,3-oxazine-2-ones, key moieties of new antiulcer agents, were prepared successfully by treating corresponding hydroxyamide with N-bromosuccinimide (NBS) and silveracetate in acetonitrile. From the fact that the methods for the preparation of hydoxy amides are versatile and such amides could be converted to the corresponding 2-oxazolid-iones and 1,3-oxazine-2-one under our reaction condition, we think that our method is very practical one for the preparation of such compounds. In addition, the above synthetic example affords a good evidence of the synthetic applicability of our improved Hofmann rearrangement.

• Biomolecules & Therapeutics
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• v.5 no.3
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• pp.246-252
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• 1997

This study was performed to evaluate antiulcer effects of traditional folk medicines such as heat-treated acumen, halloysitum rubrum and os sepiae against stomach ulcer induced by acetic acid in Sprague-Dawley rats. Various pharmacological parameters were utilized to compare the antiulcer effects of aforementioned drugs based on the size of ulcer lesion, pepsin activity, free and total acidity, gastric secretory volume, and 5-HT (hydxoytrytamine) content. All folk medicines and ranitidine as control drus were shown to decrease ulcer lesion size after 5-day treatments, with the order of halloysitum rubrum, os sepiae, heat-treated acumen and ranitidine. All treated drugs except os sepiae inhibited the gastric volume as compared with that in the control group. Ranitidine most significantly inhibited the gastric volume. All the experimented drugs in this study lowered the gastric acidity. Halloysitum rubrum decreased it most remarkably, followed by ranitidine, os sepiae and heat-treated alumen after 5-day treatments. All used drugs alleviated the pepsin activity as compared with the control group, os sepiae being the highest then halloysitum rubrum, heat-treated alumen and ranitidine in turn. Heat-treated alumen and halloysitum rubrum showed mucin production to the great extent, and ranitidine had slight increasing effect thereon. At the end of observation period, all drugs except ranitidine increased 5-HT contents as compared to the normal group. From the above results, we could confirm the folk medicines such as heat-treated alumen, halloysitum rubrum and os sepiae have not only remarkable antiulcer effects but also preventing effects for the stomach ulcer recurrence, which suggest the experimented folk medicines could be developed as new antiulcer agents.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.3
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• pp.337-343
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• 1997

Antiulcer effects of YH1238 and YH1885 were determined in the isolated gastric cells from human and rabbit stomach. Intracellular accumulation of $[^{14}C]-aminopyrine\;and\;[^{14}C]-glucose$ oxidation were used as indicators of acid secretory ability of the gastric cells. Unstimulated and stimulated gastric cells with dibutyryl cAMP$(10^{-3}M)$ were used and the inhibitory effects of YH1238 and VH1885 on acid secretion were compared with known proton pump inhibitors such as omerrazole and SK&F 96067. Dibutyryl cAMP stimulated the $[^{14}C]-aminopyrine$ accumulation and $[^{14}C]-glucose$ oxidation, which were inhibited by YH1238, YH1885, SK&F 96067 and omeprazole. Inhibitory effects of YH1238, YH1885 and omeprazole on $[^{14}C]-aminopyrine$ accumulation in stimulated gastric cells were more potent than that of SK&F 96067 at the concentration of $10^{-5}M$. It is suggested that the reversible proton pump inhibitors YH1238 and YH1885 would be effective antiulcer agents.

• Archives of Pharmacal Research
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• v.19 no.2
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• pp.126-131
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• 1996

The effects of various synthetic benzimidazole derivatives on gastric H^+/K^+$ATPase activity in vitro were examined. The results showed that the effects of substituents on the benzimidazole ring were not significant. However, replacement of sulfoxide connecting two ring systems to sulfide resulted in a completely inactive compound in vitro, suggesting the essential role of sulfoxide group in the inhibition. In addition, compounds with 5 or 6-membered oxacyclic substituents attached to the pyridine ring displayed the most effective inhibitory activity. Among these derivatives, AU-47 was the most potent, and detailed mechanistic studies with the compound were carried out. AU-47 inhibited gastricH^+/K^+$ATPase in a concentration and time dependent manner with 50% inhibition at $6\muM$. The presence of sulfhydryl reducing agents or substrate analogue protected H^+/K^+$ATPase from the inactivation. The inhibition by AU-47 was potentiated by acid pretreatment of the compound, suggesting the structural conversion of AU-47 into a more active intermediate which was favored in acidic condition. Consistent with in vitro results, AU-47 inhibited in vivo gastric acid secretion. The results suggest that AU47 is a relevant candidate for the development of new antiulcer agent.

• Archives of Pharmacal Research
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• v.21 no.1
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• pp.6-11
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• 1998

The activities of two types of antiulcer agents against 9 strains of Helicobacter pylori (H. pylori) were determined by the agar dilution method. The antiulcer agents were YJA20379, a newly synthesized proton pump inhibitor developed by Yung-jin Pharmaceutical company, and omeprazole. Both compounds were found to have significant activities against this organism. The MIC values of YJA20379 and omeprazole were 11.7 and $31.25{\mu.g/ml}$ respectively. In addition, the inhibitory potency of both compounds was investigated on H. pylori urease which is believed to be an important colonization and virulence factor in the pathogenesis of gastritis and peptic ulcers. These compounds dose-dependently inhibited urease extracted with distilled water and their $IC_50$ values were $16.4{\times}10^{-5} M and 14.3{\times}10^{-5}M,$ respectively. In addition, a pH-dependent study to determine whether inhibitory potency would be activated by acid condition was performed. It was found that unlike omeprazole, YJA20379 was not affected by acid condition. To determine the inhibition pattern and optimal concentration of substrate, kinetics were evaluated at various pH levels (pH 5.0, 7.0, and 8.5). The data show that YJA20379 noncompetitively inhibited H. pylori urease and $K_M/K_i$values were 0.96 $mM/60{\mu}M (pH 5.0), 0.56 mM/141.5 {\mu}M (pH 7.0)$, and $1.94mM/34{\mu}M (pH 8.5)$, respectively. Based on data obtained, it is concluded that YJA20379 is a significant inhibitor of H. pylori growth and urease and therefore, taking these results into consideration, YJA20379 might be a beneficial therapy for gastritis and peptic ulcers induced by H. pylori.

• Biomolecules & Therapeutics
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• v.3 no.3
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• pp.205-209
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• 1995

The novel compound KH 3218 was synthesized and evaluated for its ability to inhibit the gastric H$^{＋}$＋ $K^{＋}$ ATPase activity in vitro as well as to lessen gastric acid secretion in vivo. KH 3218 inhibited rabbit gastric H$^{＋}$＋ $K^{＋}$ ATPase in a concentration and time dependent manner. $IC_{50}$/ value was estimated to be about 15 $\mu$M. The inhibition of the H$^{＋}$＋ $K^{＋}$ ATPase by KH 3218 was blocked by sulfhydryl reducing agents, dithiothreitol or $\beta$-mercaptoethanol. The inhibition of the enzyme was not reversible by 50 fold dilution of the incubation mixtures, suggesting the irreversible nature of the inactivation. In the pylorus-ligated rift, KH 3218 reduced the total acid output as compared with the control. In addition, KH 3218 was capable of inhibiting H. pylori urease activity. These data suggest that KH 3218 is a potent inhibitor for H$^{＋}$＋ $K^{＋}$ ATPase activity as well as for gastric acid secretion, and has a potential to be developed as a novel antiulcer agent.