(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

• Published in: Journal of medicinal chemistry Vol. 35; no. 6; pp. 1049 - 1057
• Main Authors: Kohl, Bernhard, Sturm, Ernst, Senn-Bilfinger, Joerg, Simon, W. Alexander, Krueger, Uwe, Schaefer, Hartmann, Rainer, Georg, Figala, Volker, Klemm, Kurt
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.03.1992
• Subjects: 2-Pyridinylmethylsulfinylbenzimidazoles; Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphate - antagonists & inhibitors; Animals; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Dogs; Gastric Mucosa - drug effects; H(+)-K(+)-Exchanging ATPase; Omeprazole - analogs & derivatives; Pantoprazole; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Rabbits; Structure-Activity Relationship; Sulfoxides - pharmacology
• ISSN: 0022-2623; 1520-4804
• 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.