title: 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.
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.
authors.affiliation: Discovery Chemistry, Pfizer Global Research & Development, Nagoya laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawai
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ando
authors.forename: Yukari
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Isao
authors.initials: I
authors.lastname: Sakurada
authors.forename: Masako
authors.initials: M
authors.lastname: Hirota
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakamura
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ohta
authors.forename: Masaki
authors.initials: M
authors.lastname: Sudo
authors.forename: Kazunari
authors.initials: K
authors.lastname: Hattori
authors.forename: Tadashi
authors.initials: T
authors.lastname: Takashima
authors.forename: Masanori
authors.initials: M
authors.lastname: Hizue
authors.forename: Shuzo
authors.initials: S
authors.lastname: Watanabe
authors.forename: Isami
authors.initials: I
authors.lastname: Fujita
authors.forename: Mayumi
authors.initials: M
authors.lastname: Mizutani
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kawamura
mesh_terms: 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
chemical_list: 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