TY - JOUR
T1 - Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation
AU - Camps, Pelayo
AU - Formosa, Xavier
AU - Galdeano, Carles
AU - Gómez, Tània
AU - Muñoz-Torrero, Diego
AU - Scarpellini, Michele
AU - Viayna, Elisabet
AU - Badia, Albert
AU - Clos, M. Victòria
AU - Camins, Antoni
AU - Pallàs, Mercè
AU - Bartolini, Manuela
AU - Mancini, Francesca
AU - Andrisano, Vincenza
AU - Estelrich, Joan
AU - Lizondo, Mònica
AU - Bidon-Chanal, Axel
AU - Luque, F. Javier
PY - 2008/6/26
Y1 - 2008/6/26
N2 - A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced Aβ aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant Aβ antiaggregating activity, which makes them promising anti-Alzheimer drug candidates. © 2008 American Chemical Society.
AB - A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced Aβ aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant Aβ antiaggregating activity, which makes them promising anti-Alzheimer drug candidates. © 2008 American Chemical Society.
U2 - 10.1021/jm8001313
DO - 10.1021/jm8001313
M3 - Article
VL - 51
SP - 3588
EP - 3598
IS - 12
ER -