Inhibition of gastric H+,K+-ATPase by new dihydropyrazole derivative KYY-008

Takuto Fujii*, Kenji Sugimoto, Takafumi Noda, Takahiro Shimizu, Yuji Matsuya, Hideki Sakai

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The gastric proton pump (H+,K+-ATPase) responsible for the H+ secretion of gastric acid is an essential therapeutic target for acid-related diseases. H+,K+-ATPase belongs to a P2-type ATPase family. Here, we examined the effects of a newly synthesized dihydropyrazole derivative KYY-008 on the H+,K+-ATPase. KYY-008 concentration-dependently inhibited the enzyme activity of the ATPase in the membrane fractions prepared from isolated hog gastric mucosa and from human kidney HEK293 cells in which gastric H+,K+-ATPase is exogenously expressed. The IC50 values in these samples were 3.4 μM and 3.7 μM, respectively. In addition, KYY-008 significantly inhibited the H+,K+-ATPase-derived H+ uptake into the tightly sealed vesicles prepared from the hog gastric mucosa. In contrast, KYY-008 has no effect on the activities of other P2-type ATPases such as Na+,K+-ATPase and Ca2+-ATPase. KYY-008 did not change the ionic currents of voltage-dependent Ca2+ channels, that were potential targets for some dihydropyrazole derivatives. Together, we discovered a new dihydropyrazole derivative which acts as a selective inhibitor of gastric H+,K+-ATPase.

Original languageEnglish
Pages (from-to)177-182
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume567
DOIs
StatePublished - 2021/08/27

Keywords

  • Dihydropyrazole
  • Gastric proton pump
  • H,K-ATPase
  • Stomach

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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