Discovery of (-)-6-[2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl]-3,4-dihydro-2(1H)-quinolinone--a potent NR2B-selective N-methyl D-aspartate (NMDA) antagonist for the treatment of pain

Bioorg Med Chem Lett. 2007 Oct 15;17(20):5558-62. doi: 10.1016/j.bmcl.2007.08.014. Epub 2007 Aug 15.

Abstract

(-)-6-[2-[4-(3-Fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl]-3,4-dihydro-2(1H)-quinolinone was identified as an orally active NR2B-subunit selective N-methyl-d-aspartate (NMDA) receptor antagonist. It has very high selectivity for NR2B subunits containing NMDA receptors versus the HERG-channel inhibition (therapeutic index=4200 vs NR2B binding IC(50)). This compound has improved pharmacokinetic properties compared to the prototype CP-101,606.

MeSH terms

  • Animals
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Inhibitory Concentration 50
  • Molecular Structure
  • N-Methylaspartate / antagonists & inhibitors*
  • N-Methylaspartate / metabolism*
  • Pain* / drug therapy
  • Piperidines / chemistry*
  • Piperidines / pharmacology
  • Quinolones / chemistry*
  • Quinolones / pharmacology
  • Rats
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Structure-Activity Relationship

Substances

  • 6-(2-(4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl)-1-hydroxyethyl)-3,4-dihydro-2(1H)-quinolinone
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Enzyme Inhibitors
  • Ether-A-Go-Go Potassium Channels
  • NR2B NMDA receptor
  • Piperidines
  • Quinolones
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • Cytochrome P-450 CYP2D6