Abstract
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 Ki of 10 nM at pH 7. In contrast to previous P-CABs, this structure has a point positive charge (pKa 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), pKa 5.6]. The dissociation rate of the compound from the isolated ATPase is slower than other P-CABs, with the t1/2 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 MgPi. However, TAK-438 also binds enzyme at 1.3 nmol/mg in the absence of Mg2+. 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.
Footnotes
This work was supported by Takeda Pharmaceutical Company Limited; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants DK053642, DK058333, DK077149]; and a U.S. VA Merit Grant Award [I01BX001006-01].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.185314.
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ABBREVIATIONS:
- PPI
- proton pump inhibitor
- P-CAB
- potassium-competitive acid blocker
- SCH28080
- (8-benzyloxy-2-methyl-imidazo(1,2-a)pyridin-3-yl)acetonitrile
- TAK-438
- 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate
- PIPES
- 1,4-piperazinediethanesulfonic acid
- CDTA
- 1,2-cyclohexylenedinitrilotetraacetic acid
- EP
- phosphoenzyme
- TM
- transmembrane
- PEG
- polyethylene glycol
- HEK
- human embryonic kidney
- PDB
- Protein Data Bank
- PF-03716556
- N-(2-hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide
- AZD0865
- 8-[(2,6-dimethylbenzyl)amino]-N-(2-hydroxyethyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide.
- Received June 23, 2011.
- Accepted August 8, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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