Amides of xanthurenic acid as zinc-dependent inhibitors of Lp-PLA(2).

Abstract 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 Zn 2+ 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.