2-[(2-Aminobenzyl)sulfinyl]-1-(2-pyridyl)-1,4,5,6-tetrahydrocyclopent[d]imidazoles as a novel class of gastric H+/K+-ATPase inhibitors.
Substituted 2-sulfinylimidazoles were synthesized and investigated as potential inhibitors of gastric H+/K(+)-ATPase. The 4,5-unsubstituted imidazole series 6-11 and the 1,4,5,6-tetrahydrocyclopent[d]imidazole series 12 were found to be potent inhibitors of the acid secretory enzyme H+/K(+)-ATPase. Structure-activity relationships indicate that the substitution of 2-pyridyl groups at the 1-position of the imidazole moiety combined with (2-aminobenzyl)-sulfinyl groups at the 2-position leads to highly active compounds with a favorable chemical stability. Other substitution patterns in the imidazole moiety result in reducing biological activities. 2-[(2-Aminobenzyl) sulfinyl]-1-[2-(3-methylpyridyl)]-1,4,5,6-tetrahydrocyclopent++ ++ ++ [d]-imidazole (12h, T-776) was selected for further development as a potential clinical candidate. Extensive study on the acid degradation of 12h indicates a mechanism of action different from that of omeprazole, the first H+/K(+)-ATPase inhibitor introduced to the market.
Yamada
M
M
Organic Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Yura
T
T
Morimoto
M
M
Harada
T
T
Yamada
K
K
Honma
Y
Y
Kinoshita
M
M
Sugiura
M
M
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D054328:Proton Pump Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007093:Imidazoles; D054328:Proton Pump Inhibitors