Identification of benzofuran central cores for the inhibition of leukotriene A4 hydrolase

被引：13

作者：

Eccles, Wendy ^{[1
]}

Blevitt, Jonathan M. ^{[1
]}

Booker, Jamila N. ^{[1
]}

Chrovian, Christa C. ^{[1
]}

Crawford, Shelby ^{[1
]}

de Leon, Aimee Rose ^{[1
]}

Deng, Xiaohu ^{[1
]}

Fourie, Anne M. ^{[1
]}

Grice, Cheryl A. ^{[1
]}

Herman, Krystal ^{[1
]}

Karlsson, Lars ^{[1
]}

Kearney, Aaron M. ^{[1
]}

Lee-Dutra, Alice ^{[1
]}

Liang, Jimmy ^{[1
]}

Luna, Rosa ^{[1
]}

Pippel, Dan ^{[1
]}

Rao, Navin ^{[1
]}

Riley, Jason P. ^{[1
]}

Santillan, Alejandro ^{[1
]}

Savall, Brad ^{[1
]}

Tanis, Virginia M. ^{[1
]}

Xue, Xiaohua ^{[1
]}

Young, Arlene L. ^{[1
]}

机构：

[1] Janssen Res & Dev LLC, San Diego, CA 92121 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 03期

关键词：

Leukotrienes; LTA(4)H; Leukotriene A4 hydrolase; Leukotriene B4 hydrolase;

D O I：

10.1016/j.bmcl.2012.11.074

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB4. LTB4 is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH4H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB4 levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD). (c) 2012 Elsevier Ltd. All rights reserved.

引用

页码：811 / 815

页数：5

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