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Multitarget Drug Discovery for Alzheimer's Disease: Triazinones as BACE‐1 and GSK‐3β Inhibitors
Author(s) -
Prati Federica,
De Simone Angela,
Bisignano Paola,
Armirotti Andrea,
Summa Maria,
Pizzirani Daniela,
Scarpelli Rita,
Perez Daniel I.,
Andrisano Vincenza,
PerezCastillo Ana,
Monti Barbara,
Massenzio Francesca,
Polito Letizia,
Racchi Marco,
Favia Angelo D.,
Bottegoni Giovanni,
Martinez Ana,
Bolognesi Maria Laura,
Cavalli Andrea
Publication year - 2015
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201410456
Subject(s) - neuroprotection , neurodegeneration , neurotoxicity , pharmacology , drug discovery , chemistry , drug , in vitro , neuroscience , biochemistry , disease , medicine , biology , toxicity , organic chemistry
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 (IC 50 of (18.03±0.01) μ M and (14.67±0.78) μ M 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.