Discovery of Novel 6,6-Heterocycles as Transient Receptor Potential Vanilloid (TRPV1) Antagonists

被引：36

作者：

Blum, Charles A. ^{[1
]}

Caldwell, Timothy ^{[1
]}

Zheng, Xiaozhang ^{[1
]}

Bakthavatchalam, Rajagopal ^{[1
]}

Capitosti, Scott ^{[1
]}

Brielmann, Harry ^{[1
]}

De Lombaert, Stephane ^{[1
]}

Kershaw, Mark T. ^{[1
]}

Matson, David ^{[1
]}

Krause, James E. ^{[1
]}

Cortright, Daniel ^{[1
]}

Crandall, Marci ^{[1
]}

Martin, William J. ^{[2
]}

Murphy, Beth Ann ^{[2
]}

Boyce, Susan ^{[2
]}

Jones, A. Brian ^{[2
]}

Mason, Glenn ^{[2
]}

Rycroft, Wayne ^{[2
]}

Perrett, Helen ^{[2
]}

Conley, Rachael ^{[2
]}

Burnaby-Davies, Nicola ^{[2
]}

Chenard, Bertrand L. ^{[1
]}

Hodgetts, Kevin J. ^{[1
]}

机构：

[1] Neurogen Corp, Branford, CT 06405 USA

[2] Merck Sharp & Dohme Ltd, Hoddesdon EN11 9BU, Herts, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 08期

关键词：

CAPSAICIN RECEPTOR; AMMONIUM FORMATE; PAIN; ACTIVATION; SB-705498; ABT-102; CHANNEL; AMINOQUINAZOLINES; IDENTIFICATION; EFFICACY;

D O I：

10.1021/jm100051g

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund's adjuvant (CFA) induced chronic inflammatory pain after oral administration.

引用

页码：3330 / 3348

页数：19

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