2024-03-29T09:28:56Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1224772020-08-12T13:37:22Zcom_10261_86com_10261_1col_10261_339
3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease
Prati, Federica
Pérez, Daniel I.
Pérez Castillo, Ana
Martínez, Ana
Bolognesi, Maria Laura
Ministerio de Economía y Competitividad (España)
Ministerio de Ciencia y Tecnología (España)
Instituto de Salud Carlos III
Alzheimer’s disease
6-amino-3
4-dihydro-1
3,5-triazin-2(1H)-one
Drug design
Multitarget-directed ligands
Multitarget drug discovery
72 p.-7 fig.-2 tab.-4 sch. Prati, Federica et al.
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.
2015-07-14
artículo
ACS Chem. Neurosci., Article ASAP
1948-7193,
http://hdl.handle.net/10261/122477
10.1021/acschemneuro.5b00121
1948-7193
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100006280
http://dx.doi.org/10.13039/501100004587
eng
Postprint
http://dx.doi.org/ 10.1021/acschemneuro.5b00121
Sí
openAccess
American Chemical Society