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3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease

Other TitlesTriazinones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease
AuthorsPrati, Federica; Pérez, Daniel I.; Pérez Castillo, Ana ; Martínez, Ana ; Bolognesi, Maria Laura
KeywordsAlzheimer’s disease
Drug design
Multitarget-directed ligands
Multitarget drug discovery
Issue Date14-Jul-2015
PublisherAmerican Chemical Society
CitationACS Chem. Neurosci., Article ASAP
AbstractOne 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.
Description72 p.-7 fig.-2 tab.-4 sch. Prati, Federica et al.
Publisher version (URL)http://dx.doi.org/ 10.1021/acschemneuro.5b00121
Appears in Collections:(CIB) Artículos
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