A series of multi-substituted oximes were prepared and their potencies for inhibiting lipoprotein-associated phospholipase A2 (Lp-PLA2) activity were evaluated in vitro. Among them, compounds 3a, 3b, and 3m were identified to display a micromolar potency for inhibiting Lp-PLA2 in whole human plasma and isolated human LDL. Based on these results, structure–activity relationship was studied on modification of three parts of R1, R2, ...