PT - JOURNAL ARTICLE AU - Jai Moo Shin AU - Nobuhiro Inatomi AU - Keith Munson AU - David Strugatsky AU - Elmira Tokhtaeva AU - Olga Vagin AU - George Sachs TI - Characterization of a Novel Potassium-Competitive Acid Blocker of the Gastric H,K-ATPase, 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1<em>H</em>-pyrrol-3-yl]-<em>N</em>-methylmethanamine Monofumarate (TAK-438) AID - 10.1124/jpet.111.185314 DP - 2011 Nov 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 412--420 VI - 339 IP - 2 4099 - http://jpet.aspetjournals.org/content/339/2/412.short 4100 - http://jpet.aspetjournals.org/content/339/2/412.full SO - J Pharmacol Exp Ther2011 Nov 01; 339 AB - 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.