TY - JOUR T1 - 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) JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.111.185314 SP - jpet.111.185314 AU - Jai M Shin AU - Nobuhiro Inatomi AU - Keith Munson AU - David Strugatsky AU - Elmira Tokhtaeva AU - Olga Vagin AU - George Sachs Y1 - 2011/01/01 UR - http://jpet.aspetjournals.org/content/early/2011/08/09/jpet.111.185314.abstract N2 - 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]-Nmethylmethanamine (TAK-438), is strictly K+-competitive with a Ki of 10nM 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 cell compared to previous P-CABs (e.g. 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 7.5h 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, Mg-vanadate, or Mg-Pi. 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,KATPase 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 likely 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 threefold 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 as compared to previous drugs of this class. ER -