Department of Physiology and Medicine, David Geffen School of Medicine, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, 11301 Wilshire Blvd., Bldg. 113, CA 90073, USA.
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.
钾竞争酸阻滞剂（P-CAB）1-[5-（2-氟苯基）-1-（吡啶-3-基磺酰基）-1H-吡咯-3-基]-N-甲基甲胺（TAK-438）对胃 H，K-ATP 酶的抑制作用严格受 K+竞争，在 pH7 时 K i为 10 nM。与以前的 P-CAB 不同，这种结构带有一个正点电荷（pK a 9.06），与以前的 P-CAB 相比，它可以在壁细胞中更好地积累[例如，（8-苄氧基-2-甲基-咪唑并（1,2-a）吡啶-3-基）乙腈（SCH28080），pK a 5.6]。化合物从分离的 ATP 酶上的解离速率比其他 P-CAB 慢，在 20 mM KCl 中 pH7 时 t 1/2为 7.5 h。在存在 Mg-ATP、钒酸盐或 MgP（i）的情况下，TAK-438 与 H，K-ATP 酶的结合量为 2.2 nmol/mg。然而，TAK-438 也在没有 Mg 2+的情况下以 1.3 nmol/mg 结合酶。将 H，K-ATP 酶建模到同源的 Na，K-ATP 酶预测正电荷的 N-甲基氨基与 K+结合部位中带负电荷的 Glu795 接近并形成氢键，而不是以前的 P-CAB 中平面弥散的正电荷。这可能解释了缓慢的解离和高亲和力。该模型还预测 Tyr799 的羟基与 TAK-438 的磺酰基的氧之间形成氢键。Tyr799Phe 突变导致解离速率增加 3 倍，表明这种氢键也有助于缓慢的解离速率。因此，与该类别的以前药物相比，这种胃 H，K-ATP 酶的 K+竞争性抑制剂应该提供更持久的胃酸分泌抑制作用。
