title: Multitarget drug discovery for Alzheimer's disease: triazinones as BACE-1 and GSK-3β inhibitors.
abstract: Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer's disease (AD). Thus, the development of multitarget drugs which are involved in both pathways might represent a promising therapeutic strategy. Accordingly, reported here in is the discovery of 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as the first class of molecules able to simultaneously modulate BACE-1 and GSK-3β. Notably, one triazinone showed well-balanced in vitro potencies against the two enzymes (IC50 of (18.03±0.01) μM and (14.67±0.78) μM for BACE-1 and GSK-3β, respectively). In cell-based assays, it displayed effective neuroprotective and neurogenic activities and no neurotoxicity. It also showed good brain permeability in a preliminary pharmacokinetic assessment in mice. Overall, triazinones might represent a promising starting point towards high quality lead compounds with an AD-modifying potential.
authors.affiliation: Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy); Department of Pharmacy and Biotechonology, University of Bologna via Belmeloro 6/Selmi 3, 40126 Bologna (Italy).
authors.forename: Federica
authors.initials: F
authors.lastname: Prati
authors.forename: Angela
authors.initials: A
authors.lastname: De Simone
authors.forename: Paola
authors.initials: P
authors.lastname: Bisignano
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.forename: Maria
authors.initials: M
authors.lastname: Summa
authors.forename: Daniela
authors.initials: D
authors.lastname: Pizzirani
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Perez
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Ana
authors.initials: A
authors.lastname: Perez-Castillo
authors.forename: Barbara
authors.initials: B
authors.lastname: Monti
authors.forename: Francesca
authors.initials: F
authors.lastname: Massenzio
authors.forename: Letizia
authors.initials: L
authors.lastname: Polito
authors.forename: Marco
authors.initials: M
authors.lastname: Racchi
authors.forename: Angelo D
authors.initials: AD
authors.lastname: Favia
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bottegoni
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Bolognesi
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D020134:Catalytic Domain; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006207:Half-Life; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D014227:Triazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D014227:Triazines; D052247:Nitric Oxide Synthase Type II; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: drug design; drug discovery; enzymes; heterocycles; neurochemistry