TY - JOUR
T1 - Novel huprine derivatives with inhibitory activity toward β-amyloid aggregation and formation as disease-modifying anti-Alzheimer drug candidates
AU - Viayna, Elisabet
AU - Gómez, Tània
AU - Galdeano, Carles
AU - Ramírez, Lorena
AU - Ratia, Míriam
AU - Badia, Albert
AU - Clos, M. Victória
AU - Verdaguer, Ester
AU - Junyent, Félix
AU - Camins, Antoni
AU - Pallàs, Mercè
AU - Bartolini, Manuela
AU - Mancini, Francesca
AU - Andrisano, Vincenza
AU - Arce, Mariana P.
AU - Rodríguez-Franco, María Isabel
AU - Bidon-Chanal, Axel
AU - Luque, F. Javier
AU - Camps, Pelayo
AU - Muñoz-Torrero, Diego
PY - 2010/11/8
Y1 - 2010/11/8
N2 - A new family of dual binding site acetylcholinesterase (AChE) inhibitors has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced β-amyloid (Aβ) aggregation and β-secretase (BACE-1), and to cross the blood-brain barrier. The new heterodimers consist of a unit of racemic or enantiopure huprine Y or X and a donepezil-related 5,6-dimethoxy-2-[(4- piperidinyl)methyl]indane moiety as the active site and peripheral site to mid-gorge-interacting moieties, respectively, connected through a short oligomethylene linker. Molecular dynamics simulations and kinetics studies support the dual site binding to AChE. The new heterodimers are potent inhibitors of human AChE and moderately potent inhibitors of human BChE, AChE-induced and self-induced Aβ aggregation, and BACE-1, and are predicted to be able to enter the central nervous system (CNS), thus constituting promising multitarget anti-Alzheimer drug candidates with the potential to modify the natural course of this disease. Unforgettably effective: We synthesized a new family of huprine-based dual binding site acetylcholinesterase inhibitors as multipotent disease-modifying anti-Alzheimer agents. These compounds exhibit a multitarget profile, encompassing potent inhibitory activity toward acetylcholinesterase, moderate inhibitory activity of β-amyloid aggregation, BACE-1, and butyrylcholinesterase, and are predicted to be able to cross the blood-brain barrier. © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
AB - A new family of dual binding site acetylcholinesterase (AChE) inhibitors has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced β-amyloid (Aβ) aggregation and β-secretase (BACE-1), and to cross the blood-brain barrier. The new heterodimers consist of a unit of racemic or enantiopure huprine Y or X and a donepezil-related 5,6-dimethoxy-2-[(4- piperidinyl)methyl]indane moiety as the active site and peripheral site to mid-gorge-interacting moieties, respectively, connected through a short oligomethylene linker. Molecular dynamics simulations and kinetics studies support the dual site binding to AChE. The new heterodimers are potent inhibitors of human AChE and moderately potent inhibitors of human BChE, AChE-induced and self-induced Aβ aggregation, and BACE-1, and are predicted to be able to enter the central nervous system (CNS), thus constituting promising multitarget anti-Alzheimer drug candidates with the potential to modify the natural course of this disease. Unforgettably effective: We synthesized a new family of huprine-based dual binding site acetylcholinesterase inhibitors as multipotent disease-modifying anti-Alzheimer agents. These compounds exhibit a multitarget profile, encompassing potent inhibitory activity toward acetylcholinesterase, moderate inhibitory activity of β-amyloid aggregation, BACE-1, and butyrylcholinesterase, and are predicted to be able to cross the blood-brain barrier. © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
KW - acetylcholinesterase
KW - drug design
KW - inhibitors
KW - β-amyloid peptides
KW - β-secretase
U2 - 10.1002/cmdc.201000322
DO - 10.1002/cmdc.201000322
M3 - Article
VL - 5
SP - 1855
EP - 1870
IS - 11
ER -