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

AX10185, the phenyl amide of xanthurenic acid, was found to be a sub-100nM inhibitor of Lp-PLA2. However, in the presence of EDTA the inhibitory activity of AX10185 was extinguished while the enzymatic activity of Lp-PLA2 did not change. Subsequent metal screening experiments determined the inhibiti...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 22; no. 2; pp. 868 - 871
Main Authors:	Lin, Emme C.K., Hu, Yi, Amantea, Christopher M., Pham, Lan M., Cajica, Julia, Okerberg, Eric, Brown, Heidi E., Fraser, Allister, Du, Lingling, Kohno, Yasushi, Ishiyama, Junichi, Kozarich, John W., Shreder, Kevin R.
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 15-01-2012 Elsevier
Subjects:	AX10185 Biological and medical sciences Lp-PLA2 Medical sciences Pharmacology. Drug treatments Xanthurenic acid Zn2+ dependent inhibitor AX10185 Zn2+ dependent inhibitor Xanthurenic acid Lp-PLA2 dependent inhibitor Zn Inhibitor Lp-PLA Zinc II Compounds
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Summary:	AX10185, the phenyl amide of xanthurenic acid, was found to be a sub-100nM inhibitor of Lp-PLA2. However, in the presence of EDTA the inhibitory activity of AX10185 was extinguished while the enzymatic activity of Lp-PLA2 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.12.045