title: Quinazolin-4-one derivatives as selective histone deacetylase-6 inhibitors for the treatment of Alzheimer's disease.
abstract: Novel quinazolin-4-one derivatives containing a hydroxamic acid moiety were designed and synthesized. All compounds were subjected to histone deacetylase (HDAC) enzymatic assays to identify selective HDAC6 inhibitors with nanomolar IC50 values. (E)-3-(2-Ethyl-7-fluoro-4-oxo-3-phenethyl-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, 4b, is the most potent HDAC6 inhibitor (IC50, 8 nM). In vitro, these compounds induced neurite outgrowth accompanied by growth-associated protein 43 expression, and they enhanced the synaptic activities of PC12 and SH-SY5Y neuronal cells without producing toxic or mitogenic effects. Several of the compounds dramatically increased nonhistone protein acetylation, specifically of α-tubulin. Some of the more potent HDAC6 inhibitors decreased zinc-mediated β-amyloid aggregation in vitro. N-Hydroxy-3-(2-methyl-4-oxo-3-phenethyl-3,4-dihydro-quinazolin-7-yl)-acrylamide, 3f, the most promising drug candidate, selectively inhibits HDAC6 (IC50, 29 nM), practically does not affect human ether-a-go-go-related membrane channel activity (IC50 >10 μM) or cytochrome P450 activity (IC50 >6.5 μM) in vitro, and significantly improves learning-based performances of mice with β-amyloid-induced hippocampal lesions.
authors.affiliation: School of Pharmacy, College of Medicine, ‡Department of Life Science, College of Life Science, and §Center for Innovative Therapeutics Discovery, National Taiwan University , 33, LinSen South Road, Taipei 100, Taiwan, Republic of China.
authors.forename: Chao-Wu
authors.initials: CW
authors.lastname: Yu
authors.forename: Pei-Teh
authors.initials: PT
authors.lastname: Chang
authors.forename: Ling-Wei
authors.initials: LW
authors.lastname: Hsin
authors.forename: Ji-Wang
authors.initials: JW
authors.lastname: Chern
mesh_terms: D000818:Animals; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D016716:PC12 Cells; D052999:Quinazolinones / Q000494:pharmacology*; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D056572:Histone Deacetylase Inhibitors; D052999:Quinazolinones; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases