TY - JOUR
T1 - Centrally Active Multitarget Anti-Alzheimer Agents Derived from the Antioxidant Lead CR-6
AU - Pérez-Areales, F. Javier
AU - Garrido, María
AU - Aso, Ester
AU - Bartolini, Manuela
AU - De Simone, Angela
AU - Espargaró, Alba
AU - Ginex, Tiziana
AU - Sabate, Raimon
AU - Pérez, Belén
AU - Andrisano, Vincenza
AU - Puigoriol-Illamola, Dolors
AU - Pallàs, Mercè
AU - Luque, F. Javier
AU - Loza, María Isabel
AU - Brea, José
AU - Ferrer, Isidro
AU - Ciruela, Francisco
AU - Messeguer, Angel
AU - Muñoz-Torrero, Diego
N1 - Publisher Copyright:
Copyright © 2020 American Chemical Society.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/9/10
Y1 - 2020/9/10
N2 - Oxidative stress is a major pathogenic factor in Alzheimer's disease, but it should not be tackled alone rather together with other key targets to derive effective treatments. The combination of the scaffold of the polar antioxidant lead 7-methoxy-2,2-dimethylchroman-6-ol (CR-6) with that of the lipophilic cholinesterase inhibitor 6-chlorotacrine results in compounds with favorable brain permeability and multiple activities in vitro (acetylcholinesterase, butyrylcholinesterase, β-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1), and Aβ42 and tau aggregation inhibition). In in vivo studies on wild-type and APP/presenilin 1 (PS1) mice, two selected compounds were well tolerated and led to positive trends, albeit statistically nonsignificant in some cases, on memory performance, amyloid pathology (reduced amyloid burden and potentiated non-amyloidogenic APP processing), and oxidative stress (reduced cortical oxidized proteins and increased antioxidant enzymes superoxide dismutase 2 (SOD2), catalase, glutathione peroxidase 1 (GPX1), and heme oxygenase 1 (Hmox1) and transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2)). These compounds emerge as interesting brain-permeable multitarget compounds, with a potential as anti-Alzheimer agents beyond that of the original lead CR-6.
AB - Oxidative stress is a major pathogenic factor in Alzheimer's disease, but it should not be tackled alone rather together with other key targets to derive effective treatments. The combination of the scaffold of the polar antioxidant lead 7-methoxy-2,2-dimethylchroman-6-ol (CR-6) with that of the lipophilic cholinesterase inhibitor 6-chlorotacrine results in compounds with favorable brain permeability and multiple activities in vitro (acetylcholinesterase, butyrylcholinesterase, β-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1), and Aβ42 and tau aggregation inhibition). In in vivo studies on wild-type and APP/presenilin 1 (PS1) mice, two selected compounds were well tolerated and led to positive trends, albeit statistically nonsignificant in some cases, on memory performance, amyloid pathology (reduced amyloid burden and potentiated non-amyloidogenic APP processing), and oxidative stress (reduced cortical oxidized proteins and increased antioxidant enzymes superoxide dismutase 2 (SOD2), catalase, glutathione peroxidase 1 (GPX1), and heme oxygenase 1 (Hmox1) and transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2)). These compounds emerge as interesting brain-permeable multitarget compounds, with a potential as anti-Alzheimer agents beyond that of the original lead CR-6.
UR - http://www.scopus.com/inward/record.url?scp=85090869998&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.0c00528
DO - 10.1021/acs.jmedchem.0c00528
M3 - Article
C2 - 32706255
AN - SCOPUS:85090869998
SN - 0022-2623
VL - 63
SP - 9360
EP - 9390
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 17
ER -