2-((2-Pyridylmethyl)sulfinyl)benzimidazoles: Acid sensitive suicide inhibitors of the proton transport system in the parietal cell

Rackur, Gerhard; Bickel, M.; Fehlhaber, H.‐W.; Herling, Andreas W.; Hitzel, V.; Lang, Hans J.; Rösner, Manfred; Weyer, R. Vande

doi:10.1016/0006-291x(85)91703-6

Cited by 30 publications

(15 citation statements)

References 3 publications

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“…This compound, like other substituted benzimidazoles, inhibits acid secretion by blocking the K+/H' -ATPase in parietal cells (Fellenius et al, 1981;Beil & Sewing, 1984). Before these compounds can block the K+/H' -ATPase they need to be converted into the active principle, which is formed in the parietal cell tubulovesicles at a low pH (Wallmark et al, 1984;Rackur et al, 1985;Figala et al, 1986). Mercaptanes, such as P-mercaptoethanol and dithiothreitol, were found to prevent and to reverse inhibition of parietal cell acid formation and K+/H' -ATPase blockade, indicating that sulphydryl groups are most probably involved in the chemical reactions leading to inhibition of acid secretion (Wallmark et al, 1984;Im et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Effect of omeprazole on eicosanoid formation in and release from guinea‐pig gastric mucosal cells

Hell

Sewing

1987

British J Pharmacology

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1 Guinea-pig gastric mucosal cells isolated by collagenase and pronase digestion were used to study the release of prostanoids prostaglandin I2 (PGI2; measured as 6-keto PGFJ, PGE2, PGF2. and thromboxane A2 (TXA2; measured as TXB2). Lysophosphatide acyltransferase (LAT) and phospholipase A2 (PLA2) were measured in the microsomal fraction of isolated but not separated gastric cells and isolated and enriched parietal and mucous cells. 2 In all cell preparations PLA2 activity was approximately 5 times higher than that of LAT.3 Acid-activated omeprazole inhibited LAT in a concentration-dependent manner with similar IC50 values in gastric, parietal and mucous cells. It had no effect on PLA2.4 Gastric cells constantly produced PGI2, PGE2, PGF2. and TXA2. The main prostaglandins released were PGI2 and PGE2. PGF2,, and TXA2 were released in smaller quantities.5 Omeprazole dissolved in polyethylene glycol 400 (PEG) pH 2 inhibited spontaneous PGI2 release in a concentration-dependent manner with an IC50 of 14.3 ± 4.8 tiM. Only concentrations as high as 100 tLM produced a significant reduction in PGE2 release by 60%. No significant changes could be detected in the spontaneous release of PGF2C and TXA2. 6 Omeprazole dissolved in PEG pH 7 had no effect on PGI2 release except at 100 tiM which led to an insignificant decrease by 40%. 7 These data suggest that omeprazole beyond its inhibitory effect on parietal cell K+/H+ -ATPase also affects gastric mucosal prostanoid formation and release. The inhibitory effect on PGI2 does not support the view that omeprazole protects the gastric mucosa by increasing prostanoid formation.

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Section: Introductionmentioning

confidence: 99%

Effect of omeprazole on eicosanoid formation in and release from guinea‐pig gastric mucosal cells

Hell

Sewing

1987

British J Pharmacology

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“…This is probably due to a protonophore function of the benzimidazole sulfides which will be discussed in a forthcoming publication [Schudt et al, in preparation]. Since substi tuted benzimidazole sulfoxides inhibit the proton pump by reacting chemically with the SH groups of the enzyme [Im et al, 1985;Lorentzon et al, 1985;Rackur et al, 1985], the question arises as to whether the Na+/K+-ATPase might be affected as well. Although the isolated enzyme is inhibited after acid activation of the sulfoxide, but not the sul fide, organ functions which critically depend on this enzyme activity [heart: Smith et al, 1984;kidney: Duarte et al, 1971;Grantham et al, 1970;colon: Frizzell et al, 1976;Heintze et al, 1983] are not significantly affected.…”

Section: Discussionmentioning

confidence: 99%

Specificity of the Substituted Benzimidazole B 823-08: A Prodrug for Gastric Proton Pump Inhibition

Bohnenkamp¹,

Eltze²,

Heintze³

et al. 1987

Pharmacology

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Substituted benzimidazoles are potent inhibitors of the parietal cell proton pump, the H⁺/K⁺-ATPase. One member of this group, the sulfide B 823-08 (2-[(4-methoxy-3-methyl-2-pyridylmethyl)-thio]-5-trifluoromethyl-(lH)-benzimidazole) inhibits gastric acid secretion in various in vivo models, but fails to affect acid secretion in the isolated, lumen perfused mouse stomach. In contrast, the corresponding sulfoxide (B 823-10) is active under both in vivo and in vitro conditions. Since the sulfide is metabolically transformed to sulfoxide in vivo, the sulfide behaves as a prodrug of the sulfoxide. No effects of biological significance are found on organ functions which critically depend on Na⁺/K⁺-ATPase activity. This is in line with observations that the sulfoxide needs activation in an acidic environment, which constitutes the basis of its specificity for inhibiting stimulated parietal cells.

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“…Dimerization or polymerization of TMP by acid treatment is not likely to occur [2,6]. The colored TMP was quantified by absorbance at a wavelength of 410 nm with a spectrophotometer (Beckman Instrument, Inc., Fullerton).…”

Section: Iodide Uptake Inhibitionmentioning

confidence: 99%

Inhibition of Thyrocyte lodide Uptake by H+K+ATPase Inhibitor, Timoprazole.

1995

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2-((2-Pyridylmethyl)sulfinyl)benzimidazoles: Acid sensitive suicide inhibitors of the proton transport system in the parietal cell

Cited by 30 publications

References 3 publications

Effect of omeprazole on eicosanoid formation in and release from guinea‐pig gastric mucosal cells

Effect of omeprazole on eicosanoid formation in and release from guinea‐pig gastric mucosal cells

Specificity of the Substituted Benzimidazole B 823-08: A Prodrug for Gastric Proton Pump Inhibition

Inhibition of Thyrocyte lodide Uptake by H+K+ATPase Inhibitor, Timoprazole.

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