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 b-amyloid (Ab) aggregation and b-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 Ab 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.Financial support from the Ministerio de Ciencia e Innovación (CTQ2008-03768/PPQ, SAF2009-10553, SAF2009-13093, SAF2006- 01249, SAF2008-05595), Generalitat de Catalunya (2005- SGR00180, 2009-SGR00249), Instituto de Salud Carlos III (PI080400), University of Bologna (RFO), MIUR (PRIN 2007), and COST D34, and a fellowship for C.G. (IBUB) are acknowledged.Peer reviewe

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 b-amyloid (Ab) aggregation and b-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 Ab 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.Financial support from the Ministerio de Ciencia e Innovación (CTQ2008-03768/PPQ, SAF2009-10553, SAF2009-13093, SAF2006- 01249, SAF2008-05595), Generalitat de Catalunya (2005- SGR00180, 2009-SGR00249), Instituto de Salud Carlos III (PI080400), University of Bologna (RFO), MIUR (PRIN 2007), and COST D34, and a fellowship for C.G. (IBUB) are acknowledged.Peer reviewe