Novel Huprine Derivatives with Inhibitory Activity toward beta-Amyloid Aggregation and Formation as Disease-Modifying Anti-Alzheimer Drug Candidates

作者：Viayna Elisabet^*; Gomez Tania; Galdeano Carles; Ramirez Lorena; Ratia Miriam; Badia Albert; Clos M Victoria; Verdaguer Ester; Junyent Felix; Camins Antoni; Pallas Merce; Bartolini Manuela; Mancini Francesca; Andrisano Vincenza; Arce Mariana P; Rodriguez Franco Maria Isabel; Bidon Ch**** Axel; Luque F Javier; Camps Pelayo; Munoz Torrero Diego

来源：ChemMedChem, 2010, 5(11): 1855-1870.

DOI：10.1002/cmdc.201000322

• beta-amyloid peptides
• beta-secretase
• acetylcholinesterase
• drug design
• inhibitors

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 beta-amyloid (A beta) aggregation and beta-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 A beta 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.

• 出版日期2010-11-8