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| Título: | 3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease |
Otros títulos: | Triazinones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease | Autor: | Prati, Federica; Pérez, Daniel I. CSIC ORCID; Pérez Castillo, Ana CSIC ORCID; Martínez Gil, Ana CSIC ORCID ; Bolognesi, Maria Laura | Palabras clave: | Alzheimer’s disease 6-amino-3 4-dihydro-1 3,5-triazin-2(1H)-one Drug design Multitarget-directed ligands Multitarget drug discovery |
Fecha de publicación: | 14-jul-2015 | Editor: | American Chemical Society | Citación: | ACS Chem. Neurosci., Article ASAP | Resumen: | One 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. | Descripción: | 72 p.-7 fig.-2 tab.-4 sch. Prati, Federica et al. | Versión del editor: | http://dx.doi.org/ 10.1021/acschemneuro.5b00121 | URI: | http://hdl.handle.net/10261/122477 | DOI: | 10.1021/acschemneuro.5b00121 | ISSN: | 1948-7193, | E-ISSN: | 1948-7193 |
| Aparece en las colecciones: | (CIB) Artículos |
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| acs chem. neur._Martínez, Ana_2015(post).pdf | Postprint | 1,78 MB | Adobe PDF |  Visualizar/Abrir |
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