title: Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and beta-secretase.
abstract: To explore novel effective drugs for the treatment of Alzheimer's disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and beta-secretase (BACE-1) were designed based on the multi-target-directed ligands strategy. Among them, inhibitor 28 exhibited good dual potency in enzyme inhibitory potency assay (BACE-1: IC(50)=0.567 microM; AChE: IC(50)=1.83 microM), and also showed excellent inhibitory effects on Abeta production of APP transfected HEK293 cells (IC(50)=98.7 nM) and mild protective effect against hydrogen peroxide (H(2)O(2))-induced PC12 cell injury. Encouragingly, intracerebroventricular injection of 28 into amyloid precursor protein (APP) transgenic mice caused a 29% reduction of Abeta(1-40) production. Therefore, 28 was demonstrated as a good lead compound for the further study and more importantly, the strategy of AChE and BACE-1 dual inhibitors might be a promising direction for developing novel drugs for AD patients.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhu
authors.forename: Kun
authors.initials: K
authors.lastname: Xiao
authors.forename: Lanping
authors.initials: L
authors.lastname: Ma
authors.forename: Bin
authors.initials: B
authors.lastname: Xiong
authors.forename: Yan
authors.initials: Y
authors.lastname: Fu
authors.forename: Haiping
authors.initials: H
authors.lastname: Yu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Dingyu
authors.initials: D
authors.lastname: Hu
authors.forename: Hongli
authors.initials: H
authors.lastname: Peng
authors.forename: Jingya
authors.initials: J
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Gong
authors.forename: Qian
authors.initials: Q
authors.lastname: Chai
authors.forename: Xican
authors.initials: X
authors.lastname: Tang
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D002800:Cholinesterase Inhibitors; D011480:Protease Inhibitors; D000110:Acetylcholinesterase; D053829:Amyloid Precursor Protein Secretases