Multi-Target-Directed Ligands in Alzheimer's Disease Treatment

M.      Bajda; N.      Guzior; M.      Ignasik; B.      Malawska

Abstract

Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs). This methodology has been specifically developed for treatment of disorders with complex pathological mechanisms. One such disorder is Alzheimer's disease (AD), currently the most common multifactorial neurodegenerative disease. AD is related to increased levels of the amyloid β peptide (Aβ) and the hyperphosphorylated tau protein, along with loss of neurons and synapses. Moreover, there is some evidence pointing to the role of oxidative stress, metal ion deregulation, inflammation and cell cycle regulatory failure in its pathogenesis. There are many attractive targets for the development of anti-AD drugs, and the multi-factor nature of this disease calls for multi-target-directed compounds which can be beneficial for AD treatment. This review presents the discovery of dualand multi-acting anti-AD drug candidates, focusing on the novel design strategy and the compounds it yields - particularly hybrids obtained by linking structurally active moieties interacting with different targets. The first group of compounds includes cholinesterase inhibitors acting as dual binding site inhibitors and/or inhibitors with additional properties. These compounds are characterized by increased potency against acetylcholinesterase (AChE) and Aβ plaque formation with additional properties such as antioxidant activity, neuroprotective, and metal-complexing property, voltage-dependent calcium channel antagonistic activity, inhibitory activity against glutamate-induced excitotoxicity, histamine H3 receptor antagonism, cannabinoid CB1 receptor antagonism and β-secretase (BACE1) inhibition. A novel class of compounds represents the combination of dual BACE1 inhibitors with metal chelators, and dual modulators of γ-secretase with peroxisome proliferator-ativated receptor γ (PPARγ). We have reviewed the latest reports (2008-2011) presenting new multi-target-directed compounds in Alzheimer's disease treatment.

Keywords: Alzheimer's disease, multi-target-directed ligands, dual binding site cholinesterases inhibitors, β-amyloid, β-secretase, antioxidants, H3 antagonists, metal chelators