Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase

被引：35

作者：

Kirkland, Thomas A. ^{[1
]}

Adler, Marc ^{[1
]}

Bauman, John G. ^{[1
]}

Chen, Ming ^{[1
]}

Haeggstrom, Jesper Z. ^{[4
]}

King, Beverly ^{[3
]}

Kochanny, Monica J. ^{[1
]}

Liang, Amy M. ^{[2
]}

Mendoza, Lisa ^{[3
]}

Phillips, Gary B. ^{[1
]}

Thunnissen, Marjolein ^{[5
]}

Trinh, Lan ^{[2
]}

Whitlow, Marc ^{[1
]}

Ye, Bin ^{[1
]}

Ye, Hong ^{[1
]}

Parkinson, John ^{[3
]}

Guilford, William J. ^{[1
]}

机构：

[1] Berlex Biosci, Dept Med Chem, Richmond, CA 94804 USA

[2] Berlex Biosci, Dept Mol Pharmacol, Richmond, CA 94804 USA

[3] Berlex Biosci, Dept Immunol, Richmond, CA 94804 USA

[4] Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden

[5] Lund Univ, SE-22100 Lund, Sweden

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 09期

关键词：

leukotriene A4; inhibitor; crystal structure;

D O I：

10.1016/j.bmc.2008.03.042

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Leukotriene B(4) (LTB(4)) is a potent pro-inflammatory mediator that has been implicated in the pathogenesis of multiple diseases, including psoriasis, inflammatory bowel disease, multiple sclerosis and asthma. As a method to decrease the level of LTB4 and possibly identify novel treatments, inhibitors of the LTB4 biosynthetic enzyme, leukotriene A(4) hydrolase (LTA(4)-h), have been explored. Here we describe the discovery of a potent inhibitor of LTA(4)-h, arylamide of glutamic acid 4f, starting from the corresponding glycinamide 2. Analogs of 4f are then described, focusing on compounds that are both active and stable in whole blood. This effort culminated in the identification of amino alcohol 12a and amino ester 6b which meet these criteria. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：4963 / 4983

页数：21

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