ANTIULCER AGENTS - 4-SUBSTITUTED 2-GUANIDINOTHIAZOLES - REVERSIBLE, COMPETITIVE, AND SELECTIVE INHIBITORS OF GASTRIC H+,K+-ATPASE

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. © 1990, American Chemical Society. All rights reserved.