title: Antiulcer agents. 4-substituted 2-guanidinothiazoles: reversible, competitive, and selective inhibitors of gastric H+,K(+)-ATPase.
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.
authors: Central Research Division, Pfizer Inc., Groton, Connecticut 06340.
authors: J L
authors: JL
authors: LaMattina
authors: P A
authors: PA
authors: McCarthy
authors: L A
authors: LA
authors: Reiter
authors: W F
authors: WF
authors: Holt
authors: L A
authors: LA
authors: Yeh
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis*; D001667:Binding, Competitive; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D005750:Gastric Juice / Q000378:metabolism*; D005753:Gastric Mucosa / Q000201:enzymology*; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology; D017506:H(+)-K(+)-Exchanging ATPase; D066298:In Vitro Techniques; D011480:Protease Inhibitors / Q000138:chemical synthesis*; D051381:Rats; D012636:Secretory Rate / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000897:Anti-Ulcer Agents; D006146:Guanidines; D011480:Protease Inhibitors; D013844:Thiazoles; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase