N-1-Alkyl-2-oxo-2-aryl amides as novel antagonists of the TRPA1 receptor

被引：13

作者：

Vallin, Karl S. A. ^{[1
]}

Sterky, Karin J. ^{[1
]}

Nyman, Eva ^{[2
]}

Bernstrom, Jenny ^{[2
,3
]}

From, Rebecka ^{[1
]}

Linde, Christian ^{[1
]}

Minidis, Alexander B. E. ^{[1
]}

Nolting, Andreas ^{[2
,3
]}

Narhi, Katja ^{[1
]}

Santangelo, Ellen M. ^{[1
]}

Sehgelmeble, Fernando W. ^{[1
]}

Sohn, Daniel ^{[1
]}

Strindlund, Jennie ^{[4
]}

Weigelt, Dirk ^{[1
]}

机构：

[1] AstraZeneca R&D, Innovat Med, Med Chem, CNSP iMed, SE-15185 Sodertalje, Sweden

[2] AstraZeneca R&D, Innovat Med, Discovery Sci, SE-15185 Sodertalje, Sweden

[3] AstraZeneca R&D, Innovat Med, Discovery Sci, SE-43183 Molndal, Sweden

[4] AstraZeneca R&D, Innovat Med, Neurosci, CNSP iMed, SE-15185 Sodertalje, Sweden

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 17期

关键词：

Ion channel; TRPA1; Antagonist; ACTIVATE TRPA1; CHANNEL; DISCOVERY; A1;

D O I：

10.1016/j.bmcl.2012.07.032

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of potent antagonists of the ion channel transient receptor potential A1 (TRPA1) was developed by modifying lead structure 16 that was discovered by high-throughput screening. Based on lead compound 16, a SAR was established, showing a narrow region at the nitro-aromatic R-1 moiety and at the warhead, while the R-2 side had a much wider scope including ureas and carbamates. Compound 16 inhibits Ca2+-activated TRPA1 currents reversibly in whole cell patch clamp experiments, indicating that under in vivo conditions, it does not react covalently, despite its potentially electrophilic ketone. (c) 2012 Elsevier Ltd. All rights reserved.

引用

页码：5485 / 5492

页数：8

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