2-[(2-pyridylmethyl)sulfinyl]-1H-thieno[3,4-d]imidazoles. A novel class of gastric H+/K(+)-ATPase inhibitors.
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.
Weidmann
K
K
Hoechst AG, Pharma Research, Frankfurt, Germany.
Herling
A W
AW
Lang
H J
HJ
Scheunemann
K H
KH
Rippel
R
R
Nimmesgern
H
H
Scholl
T
T
Bickel
M
M
Metzger
H
H
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
D004791:Enzyme Inhibitors; D007093:Imidazoles; D000254:Sodium-Potassium-Exchanging ATPase; D009853:Omeprazole