Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20020 (adenosine triphosphatase)
 3,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have reported previously that 2-[[[3-methyl-4-(2,2,2-trifluorethoxy)-2-pyridyl]methyl] sulfinil]- 1H-benzimidazole (AG-1749) inhibits (H+ + K+)-adenosine triphosphatase after being transformed into its cyclic sulfenamide form (AG-2000) or disulfide form (AG-1812) under acidic conditions. In this study, mechanisms related to the inhibition of acid formation by AG-1749 were investigated in isolated canine parietal cells. AG-1749 suppressed the acid formation stimulated by histamine, carbachol or dibutyryl cyclic AMP with IC50 values of approximately 0.09 microM: AG-1749 being twice as potent as omeprazole. The inhibitory effect of AG-1749 was antagonized by dithiothreitol (1 mM). 2-Cyclo-hexen-1-one (3 mM) decreased cytosolic glutathione to less than 10% of control value, and caused a 3-fold increase in the inhibitory effect of AG-1749. Glutathione, however, when added exogenously, did not affect the action of AG-1749. The inhibition was reversed by removing AG-1749 from the medium or by adding dithiothreitol (1 mM). The reversal of inhibition by these two procedures was hardly affected by puromycin (100 microM) or cycloheximide (300 microM) but significantly prevented by 2-cyclo-hexen-1-one (1 mM). Exogenously added AG-2000 (10 microM) or AG-1812 (5 microM), active forms of AG-1749, did not inhibit acid formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Possible mechanism for the inhibition of acid formation by the proton pump inhibitor AG-1749 in isolated canine parietal cells. 215 97

Mechanisms related to the inhibition of (H+ + K+)-adenosine triphosphatase (ATPase) by 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl] sulfinyl]-1H-benzimidazole (AG-1749) were studied using canine gastric microsomes. AG-1749 (1-100 microM) inhibited the K+-stimulated ATP hydrolysis and vesicular accumulation of H+. AG-1749 bound to the microsomes concentration-dependently and decreased the number of free SH groups; the binding correlating with the enzyme inhibition. Both the binding and inhibition were antagonized by dithiothreitol. N-ethylmaleimide inhibited the (H+ + K+)-ATPase and decreased the binding of [14C]AG-1749 to the microsomes. The inhibitory effect of AG-1749 gradually increased with incubation time, and was enhanced by lowering the pH. AG-2000 and AG-1812, acid-induced rearrangement products of AG-1749, inhibited (H+ + K+)-ATPase potently, rapidly and independently of pH; the inhibition was antagonized by dithiothreitol. We propose that AG-1749 is transformed into its active forms within the acidic compartment of the parietal cells and that the active compounds inhibit (H+ + K+)-ATPase activity by reacting with the SH groups of the enzyme.
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PMID:Possible mechanism for the inhibition of gastric (H+ + K+)-adenosine triphosphatase by the proton pump inhibitor AG-1749. 253 17

The antisecretory and antiulcer activities of 2[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl] sulfinyl]-1H-benzimidazole (AG-1749) were investigated in dogs and rats. AG-1749 inhibited both the (H+ + K+)-adenosine triphosphatase activity in canine gastric microsomes and dibutyryl cyclic AMP-stimulated acid formation in isolated canine parietal cells and suppressed the acid secretion stimulated by histamine, pentagastrin, bethanechol or a peptone meal in Heidenhain pouch dogs; the ID50 values were between 0.2 and 0.7 mg/kg p.o. AG-1749 inhibited both the histamine-stimulated and the basal acid secretion in pylorusligated rats and prevented water immersion stress or aspirin-induced gastric lesions and mepirizole or cysteamine-induced duodenal ulcers in rats; the ID50 values were between 0.3 to 3.6 mg/kg p.o. or i.d. Furthermore, AG-1749 prevented gastric lesions induced by absolute ethanol or acidified aspirin, and accelerated the healing of acetic acid-induced gastric or duodenal ulcers in rats. The inhibitory potency of AG-1749 in dogs was much the same as that of omeprazole and about half that of ranitidine. However, it was about 2 to 10 times more potent than omeprazole and 4 to 34 times more potent than ranitidine in rats. These results suggest that AG-1749 exerts prominent antiulcer activities mainly by suppressing acid secretion via an inhibition of a proton pump in gastric parietal cells and partly by protecting the gastrointestinal mucosa against various ulcerative stimuli.
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PMID:Antisecretory and antiulcer activities of a novel proton pump inhibitor AG-1749 in dogs and rats. 253 18