Kohl B, Sturm E, Senn-Bilfinger J, Simon W A, Krüger U, Schaefer H, Rainer G, Figala V, Klemm K
Byk Gulden Pharmaceuticals, Konstanz, Germany.
J Med Chem. 1992 Mar 20;35(6):1049-57. doi: 10.1021/jm00084a010.
[(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.
[(吡啶甲基)亚磺酰基]苯并咪唑1（PSBs）是一类高效的抗分泌（H⁺，K⁺）-ATP酶抑制剂，它们需要被酸激活以形成其活性成分——环状亚磺酰胺4。体内（H⁺，K⁺）-ATP酶的选择性抑制剂仅在低pH值时产生非选择性亲硫剂4，从而避免与体内其他巯基相互作用。发生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，因为这一步既是速率决定步骤又是pH依赖性的。本研究的目的是鉴定在具有酸性pH值的刺激胃腺中具有高（H⁺，K⁺）-ATP酶抑制活性，但在中性pH值下具有低反应性（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那样。仔细研究了所有衍生物中吡啶4-甲氧基取代基两侧取代基的关键影响。引入3-甲氧基得到了具有高效力组合的抑制剂，类似于奥美拉唑和兰索拉唑，但稳定性增加。这些研究的结果是，化合物1a（国际非专利药品名称泮托拉唑）被选为候选药物，目前正在进行III期临床研究。
