-PYRIDYL)-1,4,5,6-TETRAHYDROCYCLOPENT[D]IMIDAZOLES AS A NOVEL CLASS OF GASTRIC H+ K+-ATPASE INHIBITORS/

Substituted 8-sulfinylimidazoles were synthesized and investigated as potential inhibitors of gastric H+/K+-ATPase. The 4,5-unsubstituted im idazole series 6-11 and the 1,4,5,6-tetrahydrocyclopent[d]imidazole se ries 12 were found to be potent inhibitors of the acid secretory enzym e H+/K+-ATPase. Structure-activity relationships indicate that the sub stitution of 2-pyridyl groups at the 1-position of the imidazole moiet y combined with (2-aminobenzyl)-sulfinyl groups at the 2-position lead s to highly active compounds with a favorable chemical stability. Othe r substitution patterns in the imidazole moiety result in reducing bio logical activities. pyridyl)]-1,4,5,6-tetrahydrocyclopent[d]-imidazole (12h, T-776) was selected for further development as a potential clin ical candidate. Extensive study on the acid degradation of 12h indicat es a mechanism of action different from that of omeprazole, the first H+/K+-ATPase inhibitor introduced to the market.