Mechanism of Inhibition of H+, K+-ATPase by Sodium 2-((4-(3-Methoxypropoxy)-3-methylpyridin-2-yl)methylsulfinyl)-lH- benzimidazole (E3810).

Nochi, Shigeharu; Yokoyama, Yumi; Narukawa, Megumi; Ebine, Kumiko; Murahashi, Miho; Kawakami, Yoshiyuki; Asakawa, Naoki; Satô, Tadashi

doi:10.1248/cpb.44.552

Cited by 11 publications

(4 citation statements)

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“…Rabeprazole did not show any inhibition of DDAH-1 when assayed using the secondary assay, indicating it is likely a false-positive. It is presumed that the false signal derives from the known conversion of this prodrug to a thiol-reactive species, 17 which could directly react with the methanethiol product. In contrast, the other hit, ebselen, has already been mechanistically characterized and demonstrated to be a bioavailable inhibitor of DDAH-1, with an in-cell IC 50 value of 36 ± 7 µM.…”

Section: Resultsmentioning

confidence: 99%

A Continuous, Fluorescent, High-Throughput Assay for Human Dimethylarginine Dimethylaminohydrolase-1

Linsky

Fast

2011

SLAS Discovery

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Inhibitors of human dimethylarginine dimethylaminohydrolase-1 (DDAH-1) are of therapeutic interest for controlling pathological nitric oxide production. Only a limited number of biologically useful inhibitors have been identified, so structurally diverse lead compounds are desired. In contrast with previous assays that do not possesses adequate sensitivity for optimal screening, herein is reported a high-throughput assay that uses an alternative thiol-releasing substrate, S-methyl-L-thiocitrulline, and a thiol-reactive fluorophore, 7-diethylamino-3-(4′-maleimidylphenyl)-4-methylcoumarin, to enable continuous detection of product formation by DDAH-1. The assay is applied to query two commercial libraries totaling 4,446 compounds and two representative hits are described, including a known DDAH-1 inhibitor. This is the most sensitive DDAH-1 assay reported to date, and enables screening of compound libraries using [S] =KM conditions, while displaying Z′ factors from 0.6 – 0.8. Therefore, this strategy now makes possible high-throughput screening for human DDAH-1 inhibitors in pursuit of molecular probes and drugs to control excessive nitric oxide production.

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Section: Resultsmentioning

confidence: 99%

A Continuous, Fluorescent, High-Throughput Assay for Human Dimethylarginine Dimethylaminohydrolase-1

Linsky

Fast

2011

SLAS Discovery

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“…inhibition of H + ,K + ‐ATPase) compared with OPZ, 13 , 21 , 22 and is equal to or greater in potency than OPZ in in vitro and in vivo models of gastric acid inhibition 13 , . 23 Williams et al 13 . reported that 20 mg of RPZ once daily had a significantly faster onset of antisecretory activity than 20 mg of OPZ.…”

Section: Discussionmentioning

confidence: 99%

Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH

Shirai

Furuta

Moriyama

et al. 2001

Aliment Pharmacol Ther

202

199

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Proton pump inhibitors, such as omeprazole (OPZ), lansoprazole and rabeprazole (RPZ), have been widely used as acid inhibitory agents for the treatment of upper gastrointestinal diseases. 1 OPZ is a substituted benzimidazole, which effectively inhibits gastric acid secretion by irreversibly binding to the proton pump (H + ,K + -ATPase) in gastric parietal cells, 2, 3 and is mainly metabolized by a genetically determined enzyme, S-mephenytoin-4¢-hydroxylase (CYP2C19), in the liver to hydroxyomeprazole (OH-OPZ). 4±8 OPZ is partially metabolized by CYP3A4 to omeprazole sulphone (OPZ-SFN), which is then metabolized to hydroxyomeprazole sulphone (OH-OPZ-SFN) by CYP2C19. 9 In individuals with a poor metabolizer (PM) phenotype or genotype of CYP2C19, the SUMMARY Background: Omeprazole is mainly metabolized in the liver by CYP2C19, a genetically determined enzyme, whereas rabeprazole is mainly reduced non-enzymatically and partially metabolized by CYP2C19. The therapeutic effects of rabeprazole are therefore assumed to be less affected by an individual's CYP2C19 status. Aim: To investigate the acid inhibitory effects and plasma levels of omeprazole and rabeprazole with reference to different CYP2C19 genotypes. Methods: Fifteen healthy volunteers took a daily dose of 20 mg of omeprazole or rabeprazole for 8 days. On postdose days 1 and 8, 24-h pro®les of intragastric pH were recorded and plasma concentrations of omeprazole, rabeprazole and their metabolites were determined.

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“…For activation of rabeprazole, lower hydrogen ion concentration has been reported to be necessary [26,27]. Huber et al [26] reported necessary pH levels for 50% activation of omeprazole, lansoprazole, pantoprazole and rabeprazole and indicated that rabeprazole requires a lower concentration of H + for its activation as compared to those other PPIs.…”

Section: Discussionmentioning

confidence: 99%

Effect of Timing of Proton Pump Inhibitor Administration on Acid Suppression

Furuta

Adachi²,

Aimi³

et al. 2015

Digestion

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Background: Esomeprazole has been reported to show a strong acid suppression following preprandial as compared to postprandial administration, though no known study has compared the acid suppressing effects of other proton pump inhibitors between those administrations. The aim of this study was to compare intragastric pH levels following pre- and postprandial administrations of rabeprazole and esomeprazole. Methods: In 15 Helicobacter pylori-negative healthy volunteers, we measured intragastric pH after 7 days of pre- and postprandial administrations of rabeprazole (10 mg) or esomeprazole (20 mg) using a 5-way crossover design. Results: Preprandial administration of esomeprazole showed stronger acid suppression than postprandial administration. The values for percent time at pH >4.0 over a 24-hour period increased from 45.3% with postprandial administration of esomeprazole to 54.4% with preprandial administration, while the percent time at pH >4.0 during daytime was increased to a greater extent from 51.4 to 66.5% with preprandial administration (p = 0.05). On the other hand, the acid suppressing effect of rabeprazole was not influenced by the timing of administration. Conclusions: The acid suppressing effect of esomeprazole is influenced by administration timing. In contrast, the acid suppressing effect of rabeprazole is not augmented by preprandial administration.

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Mechanism of Inhibition of H+, K+-ATPase by Sodium 2-((4-(3-Methoxypropoxy)-3-methylpyridin-2-yl)methylsulfinyl)-lH- benzimidazole (E3810).

Cited by 11 publications

References 0 publications

A Continuous, Fluorescent, High-Throughput Assay for Human Dimethylarginine Dimethylaminohydrolase-1

A Continuous, Fluorescent, High-Throughput Assay for Human Dimethylarginine Dimethylaminohydrolase-1

Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH

Effect of Timing of Proton Pump Inhibitor Administration on Acid Suppression

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