Amides of xanthurenic acid as zinc-dependent inhibitors of Lp-PLA2

被引：12

作者：

Lin, Emme C. K. ^{[1
]}

Hu, Yi ^{[1
]}

Amantea, Christopher M. ^{[1
]}

Pham, Lan M. ^{[1
]}

Cajica, Julia ^{[1
]}

Okerberg, Eric ^{[1
]}

Brown, Heidi E. ^{[1
]}

Fraser, Allister ^{[1
]}

Du, Lingling ^{[1
]}

Kohno, Yasushi ^{[2
]}

Ishiyama, Junichi ^{[2
]}

Kozarich, John W. ^{[1
]}

Shreder, Kevin R. ^{[1
]}

机构：

[1] ActivX Biosci Inc, La Jolla, CA 92037 USA

[2] Kyorin Pharmaceut Co Ltd, Discovery Res Labs, Nogi, Tochigi, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 02期

关键词：

AX10185; Xanthurenic acid; Lp-PLA(2); Zn2+ dependent inhibitor; CORONARY ATHEROSCLEROTIC PLAQUE; PHOSPHOLIPASE A(2); SERINE HYDROLASES; ARTERY-DISEASE; POTENT;

D O I：

10.1016/j.bmcl.2011.12.045

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

AX10185, the phenyl amide of xanthurenic acid, was found to be a sub-100 nM inhibitor of Lp-PLA(2). However, in the presence of EDTA the inhibitory activity of AX10185 was extinguished while the enzymatic activity of Lp-PLA(2) did not change. Subsequent metal screening experiments determined the inhibition to be Zn2+. dependent. Structure-activity relationship studies indicated the presence of the 4-hydroxy group to be critical and selected substituted phenyl, polycyclic, and cycloaliphatic amides of xanthurenic acid to be well tolerated. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：868 / 871

页数：4

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