Antiulcer agents. 4-substituted 2-guanidinothiazoles: reversible, competitive, and selective inhibitors of gastric H+,K(+)-ATPase.
Basic Information
ID: ALA1125091
Journal: J Med Chem
Title: Antiulcer agents. 4-substituted 2-guanidinothiazoles: reversible, competitive, and selective inhibitors of gastric H+,K(+)-ATPase.
Authors: LaMattina JL, McCarthy PA, Reiter LA, Holt WF, Yeh LA.
Abstract: A series of 4-substituted 2-guanidinothiazoles has been found to inhibit the gastric proton-pump enzyme H+,K(+)-ATPase. In general, these compounds were reversible inhibitors of canine gastric H+,K(+)-ATPase, competitive at the K+ site, and selective relative to canine renal Na+,K(+)-ATPase. Structure-activity relationship (SAR) studies on this series revealed no general replacement for the guanidinothiazole. On the other hand, use of pyrrolyl, phenyl, and indolyl groups as the C-4 substituent yielded active compounds. Extensive studies of substitution patterns on these 4-aryl groups led to more active compounds, but no consistent SAR became apparent. Monosubstitution of the guanidine and substitution of the thiazole at C-5 both often led to increased activity, but combining these changes generated compounds less active than the parents. Despite 100-fold improvement in in vitro inhibitory potency, only a 3-fold increase in gastric antisecretory activity in rats was observed for these agents.
CiteXplore: 2153817
DOI: 10.1021/jm00164a012
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