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

72 p.-7 fig.-2 tab.-4 sch. Prati, Federica et al.

Detalles Bibliográficos
Autores: Prati, Federica, Pérez, Daniel I., Pérez Castillo, Ana, Martínez Gil, Ana, Bolognesi, Maria Laura
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2015
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/122477
Acceso en línea:http://hdl.handle.net/10261/122477
Access Level:acceso abierto
Palabra clave:Alzheimer’s disease
6-amino-3
4-dihydro-1
3,5-triazin-2(1H)-one
Drug design
Multitarget-directed ligands
Multitarget drug discovery
id ES_0cd8b75dfbb8ffab846deb0c2fffd85d
oai_identifier_str oai:digital.csic.es:10261/122477
network_acronym_str ES
network_name_str España
repository_id_str
spelling 3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s diseaseTriazinones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s diseasePrati, FedericaPérez, Daniel I.Pérez Castillo, AnaMartínez Gil, AnaBolognesi, Maria LauraAlzheimer’s disease6-amino-34-dihydro-13,5-triazin-2(1H)-oneDrug designMultitarget-directed ligandsMultitarget drug discovery72 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.This work was supported by IIT, UNIBO, PRIN (20103W4779), MINECO (SAF2012-37979-C03-01), Ministerio de Ciencia y Tecnologia (SAF2010-16365), Instituto de Salud Carlos III, UniRimini and CIRI (PORFESR project).Peer reviewedAmerican Chemical SocietyMinisterio de Economía y Competitividad (España)Ministerio de Ciencia y Tecnología (España)Instituto de Salud Carlos IIIConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2015info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/122477reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/ 10.1021/acschemneuro.5b00121Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1224772026-05-22T06:33:51Z
dc.title.none.fl_str_mv 3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease
Triazinones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease
title 3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease
spellingShingle 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
Alzheimer’s disease
6-amino-3
4-dihydro-1
3,5-triazin-2(1H)-one
Drug design
Multitarget-directed ligands
Multitarget drug discovery
title_short 3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease
title_full 3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease
title_fullStr 3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease
title_full_unstemmed 3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease
title_sort 3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease
dc.creator.none.fl_str_mv Prati, Federica
Pérez, Daniel I.
Pérez Castillo, Ana
Martínez Gil, Ana
Bolognesi, Maria Laura
author Prati, Federica
author_facet Prati, Federica
Pérez, Daniel I.
Pérez Castillo, Ana
Martínez Gil, Ana
Bolognesi, Maria Laura
author_role author
author2 Pérez, Daniel I.
Pérez Castillo, Ana
Martínez Gil, Ana
Bolognesi, Maria Laura
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Ministerio de Ciencia y Tecnología (España)
Instituto de Salud Carlos III
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Alzheimer’s disease
6-amino-3
4-dihydro-1
3,5-triazin-2(1H)-one
Drug design
Multitarget-directed ligands
Multitarget drug discovery
topic Alzheimer’s disease
6-amino-3
4-dihydro-1
3,5-triazin-2(1H)-one
Drug design
Multitarget-directed ligands
Multitarget drug discovery
description 72 p.-7 fig.-2 tab.-4 sch. Prati, Federica et al.
publishDate 2015
dc.date.none.fl_str_mv 2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/122477
url http://hdl.handle.net/10261/122477
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/ 10.1021/acschemneuro.5b00121
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869403306914217984
score 15.811543

Similares en LA Referencia