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

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 H(3) receptor antagonism, cannabinoid CB(1) 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.

Synthesis and Multitarget Biological Profiling of a Novel Family of Rhein Derivatives As Disease-Modifying Anti-Alzheimer Agents

“…5 This novel conception of AD would allow explaining why modulation of a single target might be ineffective, whereas simultaneous modulation of several targets of the network, including Aβ, holds promise for deriving the eagerly awaited effective disease-modifying anti-Alzheimer drugs. [6][7][8][9][10] In the past years, many research groups have pursued the development of multi-target antiAlzheimer drugs as an advantageous approach over multi-target multi-drug strategies (drug cocktails and fixed-dose combinations). [11][12][13][14][15] Multi-target compounds have been usually designed to hit at least Aβ formation and aggregation and AChE activity, 16 especially prompted by the finding that AChE can bind Aβ, thereby promoting its aggregation and increasing its neurotoxicity.…”

Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer’s disease

“…When substituted by Cl (25-27), the impact was very similar to the above-mentioned results. When substituted by different halogens, the activities on AChE and BuChE were 4-Cl 27 > 4-Br 28 > 4-F 24 . Next, we synthesised several methoxyl-substituted analogues to evaluate the impact of electro-donating effect on activity.…”

“…N-(2-((1,2,3,4-tetrahydroanthracen-9-yl)amino)ethyl)cinnamamide (9 (16 (E)-3-(4-fluorophenyl)-N-(6-((1,2,3,4-tetrahydroacridin-9-yl)amino)-hexyl)acrylamide (24). Yellow powder, yield: 48%, mp 55-56 ( (27 (E)-3-(4-phenoxyphenyl)-N-(6-((1,2,3,4-tetrahydroacridin-9-yl)amino)hexyl)acrylamide (35).…”

“…Unfortunately, current ChEs inhibitors in clinical use, such as donepezil and rivastigmine, only enable a palliative treatment 23 . Considering the multifactorial nature of AD, designing multi-target-directed ligands (MTDLs) that can simultaneously regulate multiple targets in the development of AD, has emerged as a new strategy [24][25][26] , and many of MTDLs have been proved to show promising pharmacological effects on AD [27][28][29][30][31] . The enzymatic site of human AChE (hAChE) and BuChE (hBuChE) contains two binding sites: the catalytic active site (CAS) at the bottom and the peripheral anionic site (PAS) near the entrance of the gorge 32,33 .…”

Pharmacotherapy of Alzheimer’s disease: current and future trends

“…A novel class of compounds combining BACE1 inhibition with metal chelating properties has also been developed. This strategy provides for a strong pipeline of novel compounds leading to potent and promising leads as potential AD therapeutic agents [3,20].…”