Pyridazinoquinolinetriones as NMDA glycine-site antagonists with oral antinociceptive activity in a model of neuropathic pain

被引：10

作者：

Bare, Thomas M. ^{[1
]}

Brown, Dean G. ^{[1
]}

Horchler, Carey L. ^{[1
]}

Murphy, Megan ^{[1
]}

Urbanek, Rebecca A. ^{[1
]}

Alford, Vernon ^{[1
]}

Barlaam, Christine ^{[1
]}

Dyroff, Martin C. ^{[1
]}

Empfield, James B. ^{[1
]}

Forst, Janet M. ^{[1
]}

Herzog, Keith J. ^{[1
]}

Keith, Richard A. ^{[1
]}

Kirschner, Alan S. ^{[1
]}

Lee, Chi-Ming C. ^{[1
]}

Lewis, Joseph ^{[1
]}

McLaren, Frances M. ^{[1
]}

Neilson, Kathy L. ^{[1
]}

Steelman, Gary B. ^{[1
]}

Trivedi, Shephali ^{[1
]}

Vacek, Edward P. ^{[1
]}

Xiao, Wenhua ^{[1
]}

机构：

[1] AstraZeneca Pharmaceut LP, Wilmington, DE 19803 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 13期

关键词：

D O I：

10.1021/jm060212s

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones were synthesized and found to have potent activity at the glycine site of the NMDA receptor. In some cases, these compounds possessed poor aqueous solubility that may have contributed to poor rat oral bioavailability. Subsequently, compounds have been identified with improved aqueous solubility and oral bioavailability. Several of these compounds were examined in a rat chronic constrictive injury (CCI) model of neuropathic pain and found to have potent activity when dosed orally.

引用

页码：3113 / 3131

页数：19

共 45 条

[1] Pyridazino[4,5-b]quinolinediones: Novel glycine/N-methyl-D-aspartate antagonists for the treatment of stroke [J].

Bare, TM .

JOURNAL OF HETEROCYCLIC CHEMISTRY, 1998, 35 (05) :1171-1186

[2] Magnesium and MK-801 have a similar effect in two experimental models of neuropathic pain [J].

Begon, S ;

Pickering, G ;

Eschalier, A ;

Dubray, C .

BRAIN RESEARCH, 2000, 887 (02) :436-439

[3] Intrathecal administration of an NMDA or a non-NMDA receptor antagonist reduces mechanical but not thermal allodynia in a rodent model of chronic central pain after spinal cord injury [J].

Bennett, AD ;

Everhart, AW ;

Hulsebosch, CE .

BRAIN RESEARCH, 2000, 859 (01) :72-82

[4] A PERIPHERAL MONONEUROPATHY IN RAT THAT PRODUCES DISORDERS OF PAIN SENSATION LIKE THOSE SEEN IN MAN [J].

BENNETT, GJ ;

XIE, YK .

PAIN, 1988, 33 (01) :87-107

[5] The neurobiology of pain [J].

Besson, JM .

LANCET, 1999, 353 (9164) :1610-1615

[6] Synthesis of 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]-quinoline-1,4,10(5H)-triones as NMDA glycine-site antagonists [J].

Brown, DG ;

Urbanek, RA ;

Bare, TM ;

McLaren, FM ;

Horchler, CL ;

Murphy, M ;

Steelman, GB ;

Empfield, JR ;

Forst, JM ;

Herzog, KJ ;

Xiao, WH ;

Dyroff, MC ;

Lee, CMC ;

Trivedi, S ;

Neilson, KL ;

Keith, RA .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (20) :3553-3556

[7] Supraspinal vs spinal sites of the antinociceptive action of the subtype-selective NMDA antagonist ifenprodil [J].

Chizh, BA ;

Reissmüller, E ;

Schlütz, H ;

Scheede, M ;

Haase, G ;

Englberger, W .

NEUROPHARMACOLOGY, 2001, 40 (02) :212-220

[8] CONTRIBUTION OF CENTRAL NEUROPLASTICITY TO PATHOLOGICAL PAIN - REVIEW OF CLINICAL AND EXPERIMENTAL-EVIDENCE [J].

CODERRE, TJ ;

KATZ, J ;

VACCARINO, AL ;

MELZACK, R .

PAIN, 1993, 52 (03) :259-285

[9] Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A [J].

Das, S ;

Sasaki, YF ;

Rothe, T ;

Premkumar, LS ;

Takasu, M ;

Crandall, JE ;

Dikkes, P ;

Conner, DA ;

Rayudu, PV ;

Cheung, W ;

Chen, HSV ;

Lipton, SA ;

Nakanishi, N .

NATURE, 1998, 393 (6683) :377-381

[10] EVIDENCE FOR INVOLVEMENT OF N-METHYLASPARTATE RECEPTORS IN WIND-UP OF CLASS-2 NEURONS IN THE DORSAL HORN OF THE RAT [J].

DAVIES, SN ;

LODGE, D .

BRAIN RESEARCH, 1987, 424 (02) :402-406

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