title: Substituted 2-[(2-benzimidazolylsulfinyl)methyl]anilines as potential inhibitors of H+/K+ ATPase.
abstract: 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.
authors.affiliation: Searle Research and Development, Skokie, Illinois 60077.
authors.forename: G W
authors.initials: GW
authors.lastname: Adelstein
authors.forename: C H
authors.initials: CH
authors.lastname: Yen
authors.forename: R A
authors.initials: RA
authors.lastname: Haack
authors.forename: S
authors.initials: S
authors.lastname: Yu
authors.forename: G
authors.initials: G
authors.lastname: Gullikson
authors.forename: D V
authors.initials: DV
authors.lastname: Price
authors.forename: C
authors.initials: C
authors.lastname: Anglin
authors.forename: D L
authors.initials: DL
authors.lastname: Decktor
authors.forename: H
authors.initials: H
authors.lastname: Tsai
authors.forename: R H
authors.initials: RH
authors.lastname: Keith
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D017506:H(+)-K(+)-Exchanging ATPase; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase