1. 2-[(2-pyridylmethyl)sulfinyl]-1H-thieno[3,4-d]imidazoles. A novel class of gastric H+/K(+)-ATPase inhibitors.
- Author
-
Weidmann K, Herling AW, Lang HJ, Scheunemann KH, Rippel R, Nimmesgern H, Scholl T, Bickel M, and Metzger H
- Subjects
- Animals, Dogs, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Female, Imidazoles pharmacology, Male, Omeprazole pharmacology, Rats, Rats, Inbred Strains, Structure-Activity Relationship, Imidazoles chemical synthesis, Sodium-Potassium-Exchanging ATPase antagonists & inhibitors, Stomach enzymology
- 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.
- Published
- 1992
- Full Text
- View/download PDF