2-[(2-Aminobenzyl)sulfinyl]-1-(2-pyridyl)-1,4,5,6-tetrahydrocyclopent[d]imidazoles as a Novel Class of Gastric H+/K+-ATPase Inhibitors

• Published in: Journal of medicinal chemistry 1996-01, Vol.39 (2), p.596-604
• Main Authors: Yamada, Masaki, Yura, Takeshi, Morimoto, Masamichi, Harada, Tsunehiro, Yamada, Koichiro, Honma, Yasushi, Kinoshita, Mine, Sugiura, Masaki
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Digestive system; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Gastric Acid - secretion; Gastric Mucosa - drug effects; Gastric Mucosa - enzymology; Gastric Mucosa - secretion; Imidazoles - chemistry; Imidazoles - pharmacology; Male; Medical sciences; Pharmacology. Drug treatments; Proton Pump Inhibitors; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm950610n

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.