Novel huprine derivatives with inhibitory activity toward β-amyloid aggregation and formation as disease-modifying anti-Alzheimer drug candidates.
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.
Viayna
Elisabet
E
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.
Gómez
Tània
T
Galdeano
Carles
C
Ramírez
Lorena
L
Ratia
Míriam
M
Badia
Albert
A
Clos
M Victòria
MV
Verdaguer
Ester
E
Junyent
Félix
F
Camins
Antoni
A
Pallàs
Mercè
M
Bartolini
Manuela
M
Mancini
Francesca
F
Andrisano
Vincenza
V
Arce
Mariana P
MP
Rodríguez-Franco
María Isabel
MI
Bidon-Chanal
Axel
A
Luque
F Javier
FJ
Camps
Pelayo
P
Muñoz-Torrero
Diego
D
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D013329:Structure-Activity Relationship
D000634:Aminoquinolines; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D007189:Indans; C404518:huprine X; C404519:huprine Y; D002091:Butyrylcholinesterase; D053829:Amyloid Precursor Protein Secretases