Multitarget Drug Discovery for Alzheimer's Disease: Triazinones as BACE-1 and GSK-3β Inhibitors†
Federica Prati
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)
Search for more papers by this authorDr. Angela De Simone
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Department for Life Quality Studies, University of Bologna, Corso D'Augusto 237, 47921 Rimini (Italy)
Search for more papers by this authorDr. Paola Bisignano
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorDr. Andrea Armirotti
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorDr. Maria Summa
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorDr. Daniela Pizzirani
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorDr. Rita Scarpelli
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorDr. Daniel I. Perez
Centro de Investigaciones Biologica, CSIC, Ramiro de Maetzu 9, 28040 Madrid (Spain)
Search for more papers by this authorProf. Dr. Vincenza Andrisano
Department for Life Quality Studies, University of Bologna, Corso D'Augusto 237, 47921 Rimini (Italy)
Search for more papers by this authorDr. Ana Perez-Castillo
Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier 4, 28029 Madrid (Spain)
Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED) (Spain)
Search for more papers by this authorProf. Dr. Barbara Monti
Department of Pharmacy and Biotechonology, University of Bologna via Belmeloro 6/Selmi 3, 40126 Bologna (Italy)
Search for more papers by this authorFrancesca Massenzio
Department of Pharmacy and Biotechonology, University of Bologna via Belmeloro 6/Selmi 3, 40126 Bologna (Italy)
Search for more papers by this authorDr. Letizia Polito
Fondazione Golgi Cenci, Corso San Martino 10, 20081 Abbiategrasso (Milan) (Italy)
Search for more papers by this authorProf. Dr. Marco Racchi
Department of Drug Sciences—Pharmacology, University of Pavia viale Taramelli 12, 27100 Pavia (Italy)
Search for more papers by this authorDr. Angelo D. Favia
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorDr. Giovanni Bottegoni
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorProf. Dr. Ana Martinez
Centro de Investigaciones Biologica, CSIC, Ramiro de Maetzu 9, 28040 Madrid (Spain)
Search for more papers by this authorCorresponding Author
Prof. Dr. Maria Laura Bolognesi
Department of Pharmacy and Biotechonology, University of Bologna via Belmeloro 6/Selmi 3, 40126 Bologna (Italy)
Maria Laura Bolognesi, Department of Pharmacy and Biotechonology, University of Bologna via Belmeloro 6/Selmi 3, 40126 Bologna (Italy)
Andrea Cavalli, Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorCorresponding Author
Prof. Dr. Andrea Cavalli
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)
Maria Laura Bolognesi, Department of Pharmacy and Biotechonology, University of Bologna via Belmeloro 6/Selmi 3, 40126 Bologna (Italy)
Andrea Cavalli, Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorFederica Prati
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)
Search for more papers by this authorDr. Angela De Simone
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Department for Life Quality Studies, University of Bologna, Corso D'Augusto 237, 47921 Rimini (Italy)
Search for more papers by this authorDr. Paola Bisignano
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorDr. Andrea Armirotti
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorDr. Maria Summa
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorDr. Daniela Pizzirani
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorDr. Rita Scarpelli
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorDr. Daniel I. Perez
Centro de Investigaciones Biologica, CSIC, Ramiro de Maetzu 9, 28040 Madrid (Spain)
Search for more papers by this authorProf. Dr. Vincenza Andrisano
Department for Life Quality Studies, University of Bologna, Corso D'Augusto 237, 47921 Rimini (Italy)
Search for more papers by this authorDr. Ana Perez-Castillo
Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier 4, 28029 Madrid (Spain)
Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED) (Spain)
Search for more papers by this authorProf. Dr. Barbara Monti
Department of Pharmacy and Biotechonology, University of Bologna via Belmeloro 6/Selmi 3, 40126 Bologna (Italy)
Search for more papers by this authorFrancesca Massenzio
Department of Pharmacy and Biotechonology, University of Bologna via Belmeloro 6/Selmi 3, 40126 Bologna (Italy)
Search for more papers by this authorDr. Letizia Polito
Fondazione Golgi Cenci, Corso San Martino 10, 20081 Abbiategrasso (Milan) (Italy)
Search for more papers by this authorProf. Dr. Marco Racchi
Department of Drug Sciences—Pharmacology, University of Pavia viale Taramelli 12, 27100 Pavia (Italy)
Search for more papers by this authorDr. Angelo D. Favia
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorDr. Giovanni Bottegoni
Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorProf. Dr. Ana Martinez
Centro de Investigaciones Biologica, CSIC, Ramiro de Maetzu 9, 28040 Madrid (Spain)
Search for more papers by this authorCorresponding Author
Prof. Dr. Maria Laura Bolognesi
Department of Pharmacy and Biotechonology, University of Bologna via Belmeloro 6/Selmi 3, 40126 Bologna (Italy)
Maria Laura Bolognesi, Department of Pharmacy and Biotechonology, University of Bologna via Belmeloro 6/Selmi 3, 40126 Bologna (Italy)
Andrea Cavalli, Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorCorresponding Author
Prof. Dr. Andrea Cavalli
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)
Maria Laura Bolognesi, Department of Pharmacy and Biotechonology, University of Bologna via Belmeloro 6/Selmi 3, 40126 Bologna (Italy)
Andrea Cavalli, Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy)
Search for more papers by this authorWe thank S. Mandrup Bertozzi, G. Ottonello, and L. Goldoni for analytical analysis and S. Venzano for compound handling support (IIT) as well as G. Forloni and D. Albani for providing H4-APPsw cells (Mario Negri Institute). This work was supported by IIT, UNIBO, PRIN (20103W4779), MINECO (SAF2012-37979-C03-01), Ministerio de Ciencia y Tecnologia (SAF2010-16365), Instituto de Salud Carlos III, UniRimini, and CIRI (PORFESR project).
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.
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