Chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists

被引：45

作者：

Schmidt, Robert G. ^{[1
]}

Bayburt, Erol K. ^{[1
]}

Latshaw, Steven P. ^{[1
]}

Koenig, John R. ^{[1
]}

Daanen, Jerome F. ^{[1
]}

McDonald, Heath A. ^{[1
]}

Bianchi, Bruce R. ^{[1
]}

Zhong, Chengmin ^{[1
]}

Joshi, Shailen ^{[1
]}

Honore, Prisca ^{[1
]}

Marsh, Kennan C. ^{[1
]}

Lee, Chih-Hung ^{[1
]}

Faltynek, Connie R. ^{[1
]}

Gomtsyan, Arthur ^{[1
]}

机构：

[1] Abbott Labs, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 05期

关键词：

TRPV1; antagonists; Pain; Chromanyl urea; Tetrahydroquinolinyl urea; VANILLOID RECEPTOR TRPV1; A-425619 1-ISOQUINOLIN-5-YL-3-(4-TRIFLUOROMETHYL-BENZYL)-UREA; PAIN;

D O I：

10.1016/j.bmcl.2011.01.056

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that aryl substituents on the 7- or 8-position of both bicyclic scaffolds imparted the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute pain models, and compounds with the ability to cross the blood-brain barrier were shown to be highly efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as methyl can minimize the inhibition. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：1338 / 1341

页数：4

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