Multitarget Drug Discovery for Alzheimer's Disease: Triazinones as BACE‐1 and GSK‐3β Inhibitors |
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| Authors: | Federica Prati Dr Angela De?Simone Dr Paola Bisignano Dr Andrea Armirotti Dr Maria Summa Dr Daniela Pizzirani Dr Rita Scarpelli Dr Daniel I Perez Prof?Dr Vincenza Andrisano Dr Ana Perez‐Castillo Prof?Dr Barbara Monti Francesca Massenzio Dr Letizia Polito Prof?Dr Marco Racchi Dr Angelo D Favia Dr Giovanni Bottegoni Prof?Dr Ana Martinez Prof?Dr Maria Laura Bolognesi Prof?Dr Andrea Cavalli |
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| Affiliation: | 1. Istituto Italiano di Tecnologia, D3 via Morego 30, 16163 Genova (Italy);2. Department of Pharmacy and Biotechonology, University of Bologna via Belmeloro 6/Selmi 3, 40126 Bologna (Italy);3. Department for Life Quality Studies, University of Bologna, Corso D'Augusto 237, 47921 Rimini (Italy);4. Centro de Investigaciones Biologica, CSIC, Ramiro de Maetzu 9, 28040 Madrid (Spain);5. Instituto de Investigaciones Biomédicas, CSIC‐UAM, Arturo Duperier 4, 28029 Madrid (Spain);6. Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED) (Spain);7. Fondazione Golgi Cenci, Corso San Martino 10, 20081 Abbiategrasso (Milan) (Italy);8. Department of Drug Sciences—Pharmacology, University of Pavia viale Taramelli 12, 27100 Pavia (Italy) |
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| 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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| Keywords: | drug design drug discovery enzymes heterocycles neurochemistry |
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