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

AX10185, the phenyl amide of xanthurenic acid, was found to be a sub-100 nM 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.