title: Design and synthesis of imidazole and triazole derivatives as Lp-PLA₂ inhibitors and the unexpected discovery of highly potent quaternary ammonium salts.
abstract: New Lp-PLA(2) 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.
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors: Kai
authors: K
authors: Wang
authors: Wenwei
authors: W
authors: Xu
authors: Yang
authors: Y
authors: Liu
authors: Wei
authors: W
authors: Zhang
authors: Wenyi
authors: W
authors: Wang
authors: Jianhua
authors: J
authors: Shen
authors: Yiping
authors: Y
authors: Wang
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors*; D000818:Animals; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D064801:Phospholipase A2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D064801:Phospholipase A2 Inhibitors; D000644:Quaternary Ammonium Compounds; D014230:Triazoles; C029899:imidazole; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase