TY - JOUR
T1 - Multitarget drug discovery for Alzheimer's disease
T2 - Triazinones as BACE-1 and GSK-3β inhibitors
AU - Prati, Federica
AU - De Simone, Angela
AU - Bisignano, Paola
AU - Armirotti, Andrea
AU - Summa, Maria
AU - Pizzirani, Daniela
AU - Scarpelli, Rita
AU - Perez, Daniel I.
AU - Andrisano, Vincenza
AU - Perez-Castillo, Ana
AU - Monti, Barbara
AU - Massenzio, Francesca
AU - Polito, Letizia
AU - Racchi, Marco
AU - Favia, Angelo D.
AU - Bottegoni, Giovanni
AU - Martinez, Ana
AU - Bolognesi, Maria Laura
AU - Cavalli, Andrea
PY - 2015/1/26
Y1 - 2015/1/26
N2 - 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)μUM 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.
AB - 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)μUM 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.
KW - Drug design
KW - Drug discovery
KW - Enzymes
KW - Heterocycles
KW - Neurochemistry
UR - http://www.scopus.com/inward/record.url?scp=84921474414&partnerID=8YFLogxK
U2 - 10.1002/anie.201410456
DO - 10.1002/anie.201410456
M3 - Article
C2 - 25504761
AN - SCOPUS:84921474414
SN - 1433-7851
VL - 54
SP - 1578
EP - 1582
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 5
ER -