(H+,K+)-ATPASE INHIBITING 2-[(2-PYRIDYLMETHYL)SULFINYL]BENZIMIDAZOLES .4. A NOVEL SERIES OF DIMETHOXYPYRIDYL-SUBSTITUTED INHIBITORS WITH ENHANCED SELECTIVITY - THE SELECTION OF PANTOPRAZOLE AS A CLINICAL CANDIDATE
(H+,K+)-ATPASE INHIBITING 2-[(2-PYRIDYLMETHYL)SULFINYL]BENZIMIDAZOLES .4. A NOVEL SERIES OF DIMETHOXYPYRIDYL-SUBSTITUTED INHIBITORS WITH ENHANCED SELECTIVITY - THE SELECTION OF PANTOPRAZOLE AS A CLINICAL CANDIDATE
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DOI：
10.1021/jm00084a010
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发表时间：
1992-03-20
影响因子：
7.3
通讯作者：
LEACH, CA
中科院分区：
文献类型：
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作者：
KOHL, B;STURM, E;LEACH, CA
[(吡啶基甲基)亚磺酰基]苯并咪唑 1 (PSB) 是一类高效抗分泌 (H+,K+)-ATP 酶抑制剂，需要通过酸激活才能形成其活性成分环状亚磺酰胺 4。体内 (H+,K+)-ATP 酶的选择性抑制剂仅在低 pH 下产生非选择性亲硫剂 4，从而避免与体系中的其他硫醇基团相互作用。身体。 进行酸催化转化的倾向取决于参与形成 2 的官能团的亲核/亲电性质，因为该步骤既是速率决定的又是 pH 依赖性的。 本研究的目的是鉴定在酸性 pH 值的刺激胃腺中具有高 (H+,K+)-ATP 酶抑制活性，但在中性 pH 下具有低反应性（高化学稳定性）的化合物，如体外 (Na+,K+)-ATP 酶抑制活性所反映的。 仔细研究了所有衍生物中吡啶 4-甲氧基取代基侧翼取代基的关键影响。 3-甲氧基的引入使抑制剂具有与奥美拉唑和兰索拉唑相似的高效力组合，但稳定性增加。 这些研究的结果是，化合物1a（INN泮托拉唑）被选为候选药物，目前正在进行III期临床研究。
[(Pyridylmethyl)sulfinyl]benzimidazoles 1 (PSBs) are a class of highly potent antisecretory (H+,K+)-ATPase inhibitors which need to be activated by acid to form their active principle, the cyclic sulfenamide 4. Selective inhibitors of the (H+,K+)-ATPase in vivo give rise to the nonselective thiophile 4 solely at low pH, thus avoiding interaction with other thiol groups in the body. The propensity to undergo the acid-catalyzed transformation is dependent on the nucleophilic/electrophilic properties of the functional groups involved in the formation of 2 since this step is both rate-determining and pH-dependent. The aim of this study was to identify compounds with high (H+,K+)-ATPase inhibitory activity in stimulated gastric glands possessing acidic pH, but low reactivity (high chemical stability) at neutral pH as reflected by in vitro (Na+,K+)-ATPase inhibitory activity. The critical influence of substituents flanking the pyridine 4-methoxy substituent present in all derivatives was carefully studied. The introduction of a 3-methoxy group gave inhibitors possessing a combination of high potency, similar to omeprazole and lansoprazole, but increased stability. As a result of these studies, compound 1a (INN pantoprazole) was selected as a candidate drug and is currently undergoing phase III clinical studies.