(-)-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.
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Synergy between a NR2B receptor antagonist DHQ and 3-methyl-gabapentin in mice with neuropathic pain.
Eur J Pharmacol
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Discovery Biology Research, Global Research and Development, Nagoya Laboratories, Pfizer Inc, 5-2 Taketoyo, Aichi 470-2393, Japan.
The synergistic effect of a selective NR2B NMDA receptor antagonist, (-)-(R)-6-{2-[4-(3-Fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone (DHQ), and a alpha 2 delta ligand, 3-methyl-gabapentin (3M-GBP), was investigated in the mouse partial sciatic nerve model. The interaction was observed after administration of DHQ and 3M-GBP combination at fixed dose ratios of 1:10 and 1:30 and the dose-response curves shifted approximately 13- and 17-fold leftward, respectively, from the theoretical additive values. However, a fixed dose ratio of 1:50 resulted only in an additive effect.
View Article and Find Full Text PDFDiscovery 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
October 2007
Discovery Chemistry, Pfizer Global Research & Development, Nagoya laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan.
(-)-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.
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