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.
(-)-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.
Kawai
Makoto
M
Discovery Chemistry, Pfizer Global Research & Development, Nagoya laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan.
Ando
Kazuo
K
Matsumoto
Yukari
Y
Sakurada
Isao
I
Hirota
Masako
M
Nakamura
Hiroshi
H
Ohta
Atsuko
A
Sudo
Masaki
M
Hattori
Kazunari
K
Takashima
Tadashi
T
Hizue
Masanori
M
Watanabe
Shuzo
S
Fujita
Isami
I
Mizutani
Mayumi
M
Kawamura
Mitsuhiro
M
D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013329:Structure-Activity Relationship
C524665:6-(2-(4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl)-1-hydroxyethyl)-3,4-dihydro-2(1H)-quinolinone; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C121001:NR2B NMDA receptor; D010880:Piperidines; D015363:Quinolones; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D019389:Cytochrome P-450 CYP2D6