Identification and biological characterization of 6-aryl-7-isopropylquinazolinones as novel TRPV1 antagonists that are effective in models of chronic pain

被引：55

作者：

Culshaw, AJ

Bevan, S

Christiansen, M

Copp, P

Davis, A

Davis, C

Dyson, A

Dziadulewicz, EK

Edwards, L

Eggelte, H

Fox, A

Gentry, C

Groarke, A

Hallett, A

Hart, TW

Hughes, GA

Knights, S

Kotsonis, P

Lee, W

Lyothier, I

McBryde, A

McIntyre, P

Paloumbis, G

Panesar, M

Patel, S

Seiler, MP

Yaqoob, M

Zimmermann, K

机构：

[1] Novartis Inst Biomed Res, London WC1E 6BS, England

[2] Novartis Inst Biomed Res, CH-4002 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 02期

关键词：

D O I：

10.1021/jm051058x

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Vanilloid receptor I (VR1, TRPV1) is a cation-selective ion channel that is expressed on primary afferent neurons and is upregulated following inflammation and nerve damage. Blockers of this channel may have utility in the treatment of chronic nociceptive and neuropathic pain. Here, we describe the optimization from a high throughput screening hit, of a series of 6-aryl-7-isopropylquinazolinones that are TRPV1 antagonists in vitro. We also demonstrate that one compound is active in vivo against capsaicin-induced hyperalgesia and in models of neuropathic and nociceptive pain in the rat.

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页码：471 / 474

页数：4

相关论文

共 15 条

[1] The vanilloid receptor: A molecular gateway to the pain pathway [J].

Caterina, MJ ;

Julius, D .

ANNUAL REVIEW OF NEUROSCIENCE, 2001, 24 :487-517

[2] The capsaicin receptor: a heat-activated ion channel in the pain pathway [J].

Caterina, MJ ;

Schumacher, MA ;

Tominaga, M ;

Rosen, TA ;

Levine, JD ;

Julius, D .

NATURE, 1997, 389 (6653) :816-824

[3] VR1 protein expression increases in undamaged DRG neurons after partial nerve injury [J].

Hudson, LJ ;

Bevan, S ;

Wotherspoon, G ;

Gentry, C ;

Fox, A ;

Winter, J .

EUROPEAN JOURNAL OF NEUROSCIENCE, 2001, 13 (11) :2105-2114

[4] p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia [J].

Ji, RR ;

Samad, TA ;

Jin, SX ;

Schmoll, R ;

Woolf, CJ .

NEURON, 2002, 36 (01) :57-68

[5] Pharmacological management of neuropathic pain [J].

McCleane, G .

CNS DRUGS, 2003, 17 (14) :1031-1043

[6] N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl) tetrahydropyrazine-1(2H)-carbox-amide(BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties:: II.: In vivo characterization in rat models of inflammatory and neuropathic pain [J].

Pomonis, JD ;

Harrison, JE ;

Mark, L ;

Bristol, DR ;

Valenzano, KJ ;

Walker, K .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2003, 306 (01) :387-393

[7] An expeditious synthesis of 1-(4-chlorophenyl)-3,3-dimethyl-2-butanone by a ligand-free palladium-catalyzed α-arylation of pinacolone:: Scale-up and effect of base concentration [J].

Prashad, M ;

Liu, YG ;

Repic, O .

ADVANCED SYNTHESIS & CATALYSIS, 2003, 345 (04) :533-536

[8]

Rami H. K., 2004, DRUG DISCOV TODAY, V1, P97

[9] Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial [J].

Serpell, MG .

PAIN, 2002, 99 (03) :557-566

[10] Identification and biological evaluation of 4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide, a high affinity TRPV1 (VR1) vanilloid receptor antagonist [J].

Swanson, DM ;

Dubin, AE ;

Shah, C ;

Nasser, N ;

Chang, L ;

Dax, SL ;

Jetter, M ;

Breitenbucher, JG ;

Liu, CL ;

Mazur, C ;

Lord, B ;

Gonzales, L ;

Hoey, K ;

Rizzolio, M ;

Bogenstaetter, M ;

Codd, EE ;

Lee, DH ;

Zhang, SP ;

Chaplan, SR ;

Carruthers, NI .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (06) :1857-1872