title: Synthesis and structure-activity relationships of substituted 2-[(2-imidazolylsulfinyl)methyl]anilines as a new class of gastric H+/K(+)-ATPase inhibitors. II.
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.
authors.affiliation: Research Laboratories, Nippon Chemiphar Co., Ltd., Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamakawa
authors.forename: H
authors.initials: H
authors.lastname: Matsukura
authors.forename: Y
authors.initials: Y
authors.lastname: Nomura
authors.forename: M
authors.initials: M
authors.lastname: Yoshioka
authors.forename: M
authors.initials: M
authors.lastname: Masaki
authors.forename: H
authors.initials: H
authors.lastname: Harada
authors.forename: S
authors.initials: S
authors.lastname: Okabe
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002845:Chromatography; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000201:enzymology*; D017506:H(+)-K(+)-Exchanging ATPase; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D007093:Imidazoles; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase