ABSTRACT
With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.
Subject(s)
H(+)-K(+)-Exchanging ATPase/metabolism , Piperidines/chemistry , Potassium/metabolism , Proton Pump Inhibitors/chemical synthesis , Spiro Compounds/chemistry , Administration, Intravenous , Animals , Area Under Curve , Binding Sites , Drug Evaluation, Preclinical , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , H(+)-K(+)-Exchanging ATPase/chemistry , Half-Life , Histamine/toxicity , Inhibitory Concentration 50 , Molecular Docking Simulation , Naphthalenes/chemistry , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Potassium/chemistry , Proton Pump Inhibitors/chemistry , Proton Pump Inhibitors/pharmacokinetics , ROC Curve , Rats , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacokinetics , Structure-Activity RelationshipABSTRACT
A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.