title: Triazole derivatives: a series of Darapladib analogues as orally active Lp-PLA2 inhibitors.
abstract: This Letter reports our efforts towards the optimization of our previously identified series of imidazole and triazole derivatives that lead to the discovery of a series of orally active Lp-PLA2 inhibitors in C57 mice. These inhibitors are characterized by the presence of a diamine side chain in the molecules, such as 2c, 2f, and 4a. The introduction of the terminal-end amine succeeded in maintaining the in vitro activities at sub-nanomolar levels. The vivo activities could be greatly affected by variations in the two amines via modulating the metabolic stability and lipophilicity of the compounds.
authors.affiliation: 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.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Wenwei
authors.initials: W
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Mingguang
authors.initials: M
authors.lastname: Mo
authors.forename: Yiping
authors.initials: Y
authors.lastname: Wang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001547:Benzaldehydes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010091:Oximes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D004791:Enzyme Inhibitors; D010091:Oximes; D011994:Recombinant Proteins; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides