Substituted 2-[(2-benzimidazolylsulfinyl)methyl]anilines as potential inhibitors of H+/K+ ATPase

A series of substituted 2-[(2-benzimidazolylsulfinyl)methyl]anilines were synthesized as potential inhibitors of the acid secretory enzyme H+/K+ ATPase. Substitutions on the aniline nitrogen atom resulted in potent enzyme inhibition in vitro but weak activity in gastric fistula dogs. Electron-donati...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1988-06, Vol.31 (6), p.1215-1220
Main Authors: Adelstein, Gilbert W, Yen, Chung H, Haack, Richard A, Yu, Stella, Gullikson, Gary, Price, Doreen V, Anglin, Charles, Decktor, Dennis L, Tsai, Henry, Keith, Robert H
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - antagonists & inhibitors
Aniline Compounds - chemical synthesis
Aniline Compounds - pharmacology
Animals
Chemistry
Dogs
Exact sciences and technology
Female
Gastric Acid - metabolism
H(+)-K(+)-Exchanging ATPase
Heterocyclic compounds
Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings
Organic chemistry
Preparations and properties
Structure-Activity Relationship
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Summary:A series of substituted 2-[(2-benzimidazolylsulfinyl)methyl]anilines were synthesized as potential inhibitors of the acid secretory enzyme H+/K+ ATPase. Substitutions on the aniline nitrogen atom resulted in potent enzyme inhibition in vitro but weak activity in gastric fistula dogs. Electron-donating substituents on the aniline ring enhanced in vitro and in vivo potency relative to the unsubstituted analogue. The potency showed a correlation to the calculated pKa of the aniline nitrogen atom. Substitutions on the aniline and benzimidazole rings did not further enhance potency. Di- and trisubstituted aniline derivatives were potent inhibitors of the enzyme system. The preferred combination of substituents were a methoxy group on the benzimidazole ring and a single alkyl group on the aniline ring. One such compound, 76, was an effective inhibitor of acid secretion in the dog and was selected for further pharmacological study.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00401a024