title: 2-[(2-pyridylmethyl)sulfinyl]-1H-thieno[3,4-d]imidazoles. A novel class of gastric H+/K(+)-ATPase inhibitors.
abstract: 2-[(2-Pyridylmethyl)sulfinyl]thienoimidazoles were synthesized and investigated as potential inhibitors of gastric H+/K(+)-ATPase. The [3,4-d] isomers of the two possible thienoimidazole series were found to be potent inhibitors of gastric acid secretion in vitro and in vivo. Structure-activity relationships indicate that especially lipophilic alkoxy, benzyloxy, and phenoxy substituents with additional electron-demanding properties in the 4-position of the pyridine moiety combined with an unsubstituted thieno[3,4-d]imidazole lead to highly active compounds with a favorable chemical stability. Various substitution patterns in the thieno[3,4-d]imidazole moiety result in lower biological activity. The heptafluorobutyloxy derivative saviprazole (HOE 731, 5d) was selected for further development and is currently undergoing clinical evaluation. Comprehensive pharmacological studies indicate a pharmacodynamic profile different to omeprazole, the first H+/K(+)-ATPase blocker introduced on the market.
authors.affiliation: Hoechst AG, Pharma Research, Frankfurt, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Weidmann
authors.forename: A W
authors.initials: AW
authors.lastname: Herling
authors.forename: H J
authors.initials: HJ
authors.lastname: Lang
authors.forename: K H
authors.initials: KH
authors.lastname: Scheunemann
authors.forename: R
authors.initials: R
authors.lastname: Rippel
authors.forename: H
authors.initials: H
authors.lastname: Nimmesgern
authors.forename: T
authors.initials: T
authors.lastname: Scholl
authors.forename: M
authors.initials: M
authors.lastname: Bickel
authors.forename: H
authors.initials: H
authors.lastname: Metzger
mesh_terms: D000818:Animals; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D009853:Omeprazole / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013270:Stomach / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D000254:Sodium-Potassium-Exchanging ATPase; D009853:Omeprazole