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.
Makoto Kawai  1 ,  Kazuo Ando ,  Yukari Matsumoto ,  Isao Sakurada ,  Masako Hirota ,  Hiroshi Nakamura ,  Atsuko Ohta ,  Masaki Sudo ,  Kazunari Hattori ,  Tadashi Takashima ,  Masanori Hizue ,  Shuzo Watanabe ,  Isami Fujita ,  Mayumi Mizutani ,  Mitsuhiro Kawamura
Affiliations
  • 1. Discovery Chemistry, Pfizer Global Research & Development, Nagoya laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan.
PMID: 17766106 DOI: 10.1016/j.bmcl.2007.08.014
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.