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

• 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: England Elsevier Ltd 15-01-2012
• Subjects: 1-Alkyl-2-acetylglycerophosphocholine Esterase - antagonists & inhibitors; 1-Alkyl-2-acetylglycerophosphocholine Esterase - metabolism; amides; Amides - chemistry; Dose-Response Relationship, Drug; EDTA (chelating agent); enzyme activity; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Molecular Structure; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; screening; Structure-Activity Relationship; structure-activity relationships; Xanthurenates - chemistry; xanthurenic acid; zinc; Zinc - chemistry
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.12.045

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.