Discovery, synthesis, and structure-activity relations of 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-ones as potassium-competitive acid blockers

Bioorg Med Chem. 2017 Jul 15;25(14):3719-3735. doi: 10.1016/j.bmc.2017.05.012. Epub 2017 May 6.

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.

Keywords: 3,4-Dihydro-1H-spiro[naphthalene-2,2′-piperidin]-1-one derivatives; Docking analysis; H(+),K(+)-ATPase; Potassium-competitive acid blockers; S-Enantiomer.

MeSH terms

  • 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
  • H(+)-K(+)-Exchanging ATPase / metabolism*
  • Half-Life
  • Histamine / toxicity
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Naphthalenes / chemistry
  • Piperidines / chemical synthesis
  • Piperidines / chemistry*
  • Piperidines / pharmacokinetics
  • Potassium / chemistry
  • Potassium / metabolism*
  • Proton Pump Inhibitors / chemical synthesis*
  • Proton Pump Inhibitors / chemistry
  • Proton Pump Inhibitors / pharmacokinetics
  • ROC Curve
  • Rats
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry*
  • Spiro Compounds / pharmacokinetics
  • Structure-Activity Relationship

Substances

  • N-(1'-(2-(2-methylphenyl)ethyl)-1-oxo-3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-6-yl)acetamide
  • Naphthalenes
  • Piperidines
  • Proton Pump Inhibitors
  • Spiro Compounds
  • naphthalene
  • piperidine
  • Histamine
  • H(+)-K(+)-Exchanging ATPase
  • Potassium