Novel huprine derivatives with inhibitory activity toward β-amyloid aggregation and formation as disease-modifying anti-Alzheimer drug candidates

Elisabet Viayna, Tània Gómez, Carles Galdeano, Lorena Ramírez, Míriam Ratia, Albert Badia, M. Victória Clos, Ester Verdaguer, Félix Junyent, Antoni Camins, Mercè Pallàs, Manuela Bartolini, Francesca Mancini, Vincenza Andrisano, Mariana P. Arce, María Isabel Rodríguez-Franco, Axel Bidon-Chanal, F. Javier Luque, Pelayo Camps, Diego Muñoz-Torrero

Research output: Contribution to journalArticleResearchpeer-review

55 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1855-1870
JournalChemMedChem
Volume5
Issue number11
DOIs
Publication statusPublished - 8 Nov 2010

Keywords

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

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