Multitarget Anti-Alzheimer Hybrid Compounds

The difficult-to-refuse argument that simultaneous modulation of several key biological targets of a complex pathological network can lead to more efficient therapies than those afforded by single-target drugs has prompted very intense research activity, especially in academia. The Alzheimer’s disease (AD) drug discovery arena is one of the fields where the development of multitarget therapies has been most vigorously pursued in the past decade. The combination of two or more distinct pharmacophoric moieties in a single hybrid molecule represents the most usual way to build multitarget anti-Alzheimer drug candidates. Using this approach, a plethora of structural classes has been rationally designed, synthesized, and tested in vitro against the planned biological targets and, often, screened against additional proteins or pathological events of interest. As a result, hundreds of compounds with more or less in vitro balanced potencies against several key targets in AD have been identified. However, no rationally designed multitarget compound has been approved so far for the treatment of AD. The lack of clinical evidence might cast doubts on this therapeutic approach. However, one of such purposedly designed multitarget drug candidates, namely ladostigil, is currently undergoing clinical trials, whereas other hybrid compounds have been tested in different animal models of AD. In this chapter, the design and the activity profile of several examples of multitarget hybrid compounds will be discussed, with particular focus on the correlation between their in vitro and in vivo activities and the relevance of the latter for a potential treatment of AD.