Multi-Target-Directed Ligands in Alzheimer’s Disease Therapy

Abstract

So far, the only clinically approved drugs that are effective in Alzheimer's disease (AD) are those neurotransmitters oriented in their mode of action and focus, in particular, on the functional significance of acetylcholine or glutamate in the brain. Current AD drugs can, therefore, reduce the severity of cognitive symptoms, improve the quality of life, and stabilize the symptoms for some years, but they are not able to significantly modify the course of the disease. Complex disorders such as neurodegenerative diseases tend to result from multiple molecular abnormalities, not from a single defect. Moreover, a single target is unlikely to help in such cases because the cells can often find ways to compensate for a protein whose activity is affected by a drug. Thus, these limitations of the conventional "one-target, one-molecule" paradigm have triggered a recent shift in efforts to create drugs that hit more than one target simultaneously. The term multi-target-directed ligands (MTDLs) have been proposed to describe these hybrid molecules that are effective in treating complex diseases. Within our contribution, we would like to present general overview of MTDL design strategy in AD therapy, its positives and negatives, and finally summary of such multipotent compounds evaluated in clinical trials.