Characterization of a novel potassium-competitive acid blocker of the gastric H,K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438)

J Pharmacol Exp Ther. 2011 Nov;339(2):412-20. doi: 10.1124/jpet.111.185314. Epub 2011 Aug 9.


Inhibition of the gastric H,K-ATPase by the potassium-competitive acid blocker (P-CAB) 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (TAK-438), is strictly K(+)-competitive with a K(i) of 10 nM at pH 7. In contrast to previous P-CABs, this structure has a point positive charge (pK(a) 9.06) allowing for greater accumulation in parietal cells compared with previous P-CABs [e.g., (8-benzyloxy-2-methyl-imidazo(1,2-a)pyridin-3-yl)acetonitrile (SCH28080), pK(a) 5.6]. The dissociation rate of the compound from the isolated ATPase is slower than other P-CABs, with the t(1/2) being 7.5 h in 20 mM KCl at pH 7. The stoichiometry of binding of TAK-438 to the H,K-ATPase is 2.2 nmol/mg in the presence of Mg-ATP, vanadate, or MgP(i). However, TAK-438 also binds enzyme at 1.3 nmol/mg in the absence of Mg(2+). Modeling of the H,K-ATPase to the homologous Na,K-ATPase predicts a close approach and hydrogen bonding between the positively charged N-methylamino group and the negatively charged Glu795 in the K(+)-binding site in contrast to the planar diffuse positive charge of previous P-CABs. This probably accounts for the slow dissociation and high affinity. The model also predicts hydrogen bonding between the hydroxyl of Tyr799 and the oxygens of the sulfonyl group of TAK-438. A Tyr799Phe mutation resulted in a 3-fold increase of the dissociation rate, showing that this hydrogen bonding also contributes to the slow dissociation rate. Hence, this K(+)-competitive inhibitor of the gastric H,K-ATPase should provide longer-lasting inhibition of gastric acid secretion compared with previous drugs of this class.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acridine Orange / metabolism
  • Animals
  • Fluorescent Dyes / metabolism
  • Gastroesophageal Reflux / drug therapy
  • H(+)-K(+)-Exchanging ATPase / chemistry
  • H(+)-K(+)-Exchanging ATPase / metabolism
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Molecular Targeted Therapy
  • Phosphorylation / drug effects
  • Protein Binding
  • Proton Pump Inhibitors* / analysis
  • Proton Pump Inhibitors* / chemistry
  • Proton Pump Inhibitors* / pharmacology*
  • Pyrroles / chemistry
  • Pyrroles / metabolism
  • Pyrroles / pharmacology*
  • Software
  • Stereoisomerism
  • Stomach / drug effects*
  • Stomach / enzymology
  • Sulfonamides / chemistry
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology*
  • Swine


  • 1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine
  • Fluorescent Dyes
  • Proton Pump Inhibitors
  • Pyrroles
  • Sulfonamides
  • H(+)-K(+)-Exchanging ATPase
  • Acridine Orange