Synthesis and structure-activity relationships of substituted 2-[(2-imidazolylsulfinyl)methyl]anilines as a new class of gastric H+/K(+)-ATPase inhibitors. II

Chem Pharm Bull (Tokyo). 1992 Mar;40(3):675-82. doi: 10.1248/cpb.40.675.

Abstract

A series of 2-[(2-imidazolylsulfinyl)methyl]anilines (2) having various substituents on their imidazole and aniline rings was synthesized and examined for their H+/K(+)-ATPase (adenosine triphosphatase) inhibitory effects and antisecretory activity against histamine-stimulated gastric acid secretions in Heidenhain pouch dogs. Although substitutions on the imidazole ring did not enhance biological activity, substitutions on the aniline ring by electron-donating substituents potently enhanced the enzyme inhibitory activity and also showed an inhibitory effect on histamine-stimulated gastric acid secretion after oral administration. In particular, the in vitro activity of the dimethyl (2u--w) and trimethyl (2ac) derivatives was about 10 times that of omeprazole. Also, 4-methyl (2k), 4-methoxy-5-methyl (2y) and 3,5-dimethyl-4-methoxy (2ab) derivatives showed a potent antisecretory effect of more than 80% after oral administration at 6 mg/kg. Although these aniline derivatives have relatively low stabilities in aqueous solution, replacement of the isobutyl group at the aniline nitrogen atom with N-(2-methoxyethyl) group enhanced the stability.

MeSH terms

  • Adenosine Triphosphatases / antagonists & inhibitors*
  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology
  • Animals
  • Chromatography
  • Dogs
  • Gastric Acid / metabolism*
  • Gastric Mucosa / enzymology*
  • H(+)-K(+)-Exchanging ATPase
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Spectrophotometry, Infrared
  • Structure-Activity Relationship

Substances

  • Aniline Compounds
  • Imidazoles
  • Adenosine Triphosphatases
  • H(+)-K(+)-Exchanging ATPase