title: 5-((3-Amidobenzyl)oxy)nicotinamides as Sirtuin 2 Inhibitors.
abstract: Derived from our previously reported human sirtuin 2 (SIRT2) inhibitors that were based on a 5-aminonaphthalen-1-yloxy nicotinamide core structure, 5-((3-amidobenzyl)oxy)nicotinamides offered excellent activity against SIRT2 and high isozyme selectivity over SIRT1 and SIRT3. Selected compounds also exhibited generally favorable in vitro absorption, distribution, metabolism, and excretion properties. Kinetic studies revealed that a representative SIRT2 inhibitor acted competitively against both NAD(+) and the peptide substrate, an inhibitory modality that was supported by our computational study. More importantly, two selected compounds exhibited significant protection against α-synuclein aggregation-induced cytotoxicity in SH-SY5Y cells. Therefore, 5-((3-amidobenzyl)oxy)nicotinamides represent a new class of SIRT2 inhibitors that are attractive candidates for further lead optimization in our continued effort to explore selective inhibition of SIRT2 as a potential therapy for Parkinson's disease.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , 516 Delaware Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Teng
authors.initials: T
authors.lastname: Ai
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , 516 Delaware Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , 516 Delaware Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Swati S
authors.initials: SS
authors.lastname: More
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , 516 Delaware Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Jiashu
authors.initials: J
authors.lastname: Xie
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , 516 Delaware Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D004285:Dogs; D004355:Drug Stability; D006801:Humans; D007700:Kinetics; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D009536:Niacinamide / Q000737:chemistry*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*; D037761:Sirtuins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D051844:alpha-Synuclein / Q000378:metabolism / Q000633:toxicity
chemical_list: D051844:alpha-Synuclein; D009536:Niacinamide; C474199:SIRT2 protein, human; C508544:SIRT5 protein, human; D056565:Sirtuin 2; D037761:Sirtuins