Design and synthesis of imidazole and triazole derivatives as Lp-PLA2 inhibitors and the unexpected discovery of highly potent quaternary ammonium salts

New Lp-PLA2 inhibitors were synthesized by the bioisosteric replacement of the amide group of Darapladib with an imidazole or a triazole. Unfortunately, the inhibitory activities of these derivatives were lower than that of Darapladib. But interestingly, a series of quaternary ammonium salts that were isolated as by-products during this synthetic work were found with high potency. Of these by-products, compound 22c showed a similar profile to Darapladib both in vitro and in vivo.