title: 3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the First Dual BACE-1/GSK-3β Fragment Hits against Alzheimer's Disease.
abstract: One of the main obstacles toward the discovery of effective anti-Alzheimer drugs is the multifactorial nature of its etiopathology. Therefore, the use of multitarget-directed ligands has emerged as particularly suitable. Such ligands, able to modulate different neurodegenerative pathways, for example, amyloid and tau cascades, as well as cognitive and neurogenic functions, are fostered to come. In this respect, we report herein on the first class of BACE-1/GSK-3β dual inhibitors based on a 3,4-dihydro-1,3,5-triazin-2(1H)-one skeleton, whose hit compound 1 showed interesting properties in a preliminary investigation. Notably, compound 2, endowed with well-balanced potencies against the two isolated enzymes (IC50 of 16 and 7 μM against BACE-1 and GSK-3β, respectively), displayed effective neuroprotective and neurogenic activities and no neurotoxicity in cell-based assays. It also showed good brain permeability in a pharmacokinetic assessment in mice. Overall, triazinone derivatives, thanks to the simultaneous modulation of multiple points of the diseased network, might emerge as suitable candidates to be tested in in vivo Alzheimer's disease models.
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , 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.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.|Department for Life Quality Studies, University of Bologna , Corso D'Augusto 237, 47921 Rimini, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: De Simone
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Summa
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pizzirani
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.
authors.forename: Sine Mandrup
authors.initials: SM
authors.lastname: Bertozzi
authors.affiliation: Centro de Investigaciones Biologicas, CIB-CSIC, Ramiro de Maetzu 9, 28040 Madrid, Spain.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Perez
authors.affiliation: Department for Life Quality Studies, University of Bologna , Corso D'Augusto 237, 47921 Rimini, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.affiliation: Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier, 4, 28029 Madrid, Spain.|Centro Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) , Nicolás Cabrera, 1, Campus de Cantoblanco, 28049 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Perez-Castillo
authors.affiliation: Department of Pharmacy and Biotechonology, University of Bologna , via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Monti
authors.affiliation: Department of Pharmacy and Biotechonology, University of Bologna , via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Massenzio
authors.affiliation: Fondazione Golgi Cenci, Corso San Martino 10, 20081 Abbiategrasso, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Polito
authors.affiliation: Department of Drug Sciences-Pharmacology, University of Pavia , viale Taramelli 12, 27100 Pavia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Racchi
authors.affiliation: Department of Chemistry "Giacomo Ciamician", University of Bologna , via Selmi 2, 40126 Bologna, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Sabatino
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bottegoni
authors.affiliation: Centro de Investigaciones Biologicas, CIB-CSIC, Ramiro de Maetzu 9, 28040 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.|Department of Pharmacy and Biotechonology, University of Bologna , via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.affiliation: Department of Pharmacy and Biotechonology, University of Bologna , via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Bolognesi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005910:Glioma / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009457:Neuroglia / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014404:Tubulin / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D014150:Antipsychotic Agents; D008070:Lipopolysaccharides; D014227:Triazines; D014404:Tubulin; C000605506:GSK3B protein, human; 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; C509281:Bace1 protein, rat
keywords: 6-amino-3,4-dihydro-1,3,5-triazin-2(1H)-one; Alzheimer’s disease; drug design; glycogen-synthase kinase-3β; multitarget drug discovery; multitarget-directed ligands; β-secretase