Multitargeted design strategy for Alzheimer’s drugs: focus on anticholinesterase and antiamyloid activities

Alzheimer’s disease (AD) is a complex multifactorial syndrome where genetic predisposition interacts with environmental factors. Currently, AD pharmacotherapy relies on acethylcholinesterase inhibitors (AChEIs), valuable in restoring the cholinergic dysfunction, and memantine, a non competitive NMDA receptor antagonist that limits glutamate excitotoxicity. Despite considerable scientific progress, current drugs, developed according to the classic drug discovery paradigm of “one-molecule-one target”, offer only limited and transient benefits to patients. Therefore, in response to the molecular complexity of AD, a new strategy has recently emerged, that is the development of single chemical entities able to modulate multiple pathogenetic factors involved in the neurodegenerative process. This has led to a new paradigm in medicinal chemistry, the “multi-target directed ligands” (MTDLs) design strategy, that has already been exploited at both academic and industrial levels [1]. As in any drug discovery process, selecting optimal targets is a critical step and an important criterion for determining the success of new MTDLs. In our first attempts to design MTDLs, we focused on acetylcholinesterase (AChE), since the report that it plays other roles in addition to its ‘classical’ function in terminating cholinergic impulse, renewed the interest in AChEIs drug discovery [2]. In the years, the amyloid hypothesis has dominated the field of AD research and has provided the intellectual framework for therapeutic intervention. However, the view that Aβ is one of the factors, and not the only factor underlying AD pathogenesis, is more consistent with current knowledge, and may account for the failure of purely anti-amyloid strategies [3]. These considerations prompted us to develop new MTDLs possessing AChE inhibitory activity together with the ability to modulate Aβ secretion and aggregation. Starting from lead candidates memoquin and bis(7)-tacrine, for which a multimodal profile has been previously disclosed, two novel series of dual anticholinesterase and antiamyloid compounds have been designed and synthesized. The biological profile of the new derivatives against human cholinesterases (acetyl- and butyrylcholinesterase), Aβ aggregation promoted by AChE, self induced Aβ aggregation and BACE-1 was investigated. [1] Cavalli et al. (2008) Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem. 51, 347-372. [2] Galdeano et al. (2010) Structural determinants of the multifunctional profile of dual binding site acetylcholinesterase inhibitors as anti-Alzheimer agents. Curr. Pharm. Des. 16, 2818-2836. [3] Pimplikar (2009) Reassessing the amyloid cascade hypothesis of Alzheimer’s disease. Int. J. Biochem. Cell. Biol. 41, 1261-1268