Antiulcer agents. 4-substituted 2-guanidinothiazoles: reversible, competitive, and selective inhibitors of gastric H+,K(+)-ATPase.

Publication Type
Journal Article
Year of Publication
LaMattina, J L; McCarthy, P A; Reiter, L A; Holt, W F; Yeh, L A
J Med Chem
Date Published
1990 Feb
Adenosine Triphosphatases; Animals; Anti-Ulcer Agents; Binding, Competitive; Cattle; Chemical Phenomena; Chemistry; Gastric Juice; Gastric Mucosa; Guanidines; H(+)-K(+)-Exchanging ATPase; In Vitro Techniques; Protease Inhibitors; Rats; Secretory Rate; Structure-Activity Relationship; Thiazoles

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.