A New Series of Aryloxyacetic Acids Endowed with Multi-Target Activity towards Peroxisome Proliferator-Activated Receptors (PPARs), Fatty Acid Amide Hydrolase (FAAH), and Acetylcholinesterase (AChE).

Rosalba Leuci,Fulvio Loiodice,Antonio Carrieri,Leonardo Pisani,Luca Piemontese,Antonio Laghezza,Leonardo Brunetti,Paolo Tortorella,Marco Catto

doi:10.3390/molecules27030958

Abstract

A new series of aryloxyacetic acids was prepared and tested as peroxisome proliferator-activated receptors (PPARs) agonists and fatty acid amide hydrolase (FAAH) inhibitors. Some compounds exhibited an interesting dual activity that has been recently proposed as a new potential therapeutic strategy for the treatment of Alzheimer’s disease (AD). AD is a multifactorial pathology, hence multi-target agents are currently one of the main lines of research for the therapy and prevention of this disease. Given that cholinesterases represent one of the most common targets of recent research, we decided to also evaluate the effects of our compounds on the inhibition of these specific enzymes. Interestingly, two of these compounds, (S)-5 and 6, showed moderate activity against acetylcholinesterase (AChE) and even some activity, although at high concentration, against Aβ peptide aggregation, thus demonstrating, in agreement with the preliminary dockings carried out on the different targets, the feasibility of a simultaneous multi-target activity towards PPARs, FAAH, and AChE. As far as we know, these are the first examples of molecules endowed with this pharmacological profile that might represent a promising line of research for the identification of novel candidates for the treatment of AD.

Highlights

Peroxisome proliferator-activated receptors (PPARs) control important metabolic functions in the body and are mainly implicated in lipid and glucose homeostasis, insulin sensitivity, and energetic metabolism
As far as we know, these are the first examples of molecules endowed with this pharmacological profile, paving the way to a promising, yet unexplored, line of research for the identification of novel candidate drugs for the treatment of Alzheimer’s disease
The molecular scaffold of 5 and 11 in both enantiomeric forms (Figure 2) was used as a three-dimensional scavenger to probe the capability of these aryloxyacetic acids to fit the binding sites of the aforementioned target proteins; to get a proper metric in the evaluation of the attained data, the reference compounds Wy-14,643, rosiglitazone, JZL195, and donepezil were enrolled in this docking campaign

Summary

Introduction

Peroxisome proliferator-activated receptors (PPARs) control important metabolic functions in the body and are mainly implicated in lipid and glucose homeostasis, insulin sensitivity, and energetic metabolism. PPARs have become a useful therapeutic target for the treatment of metabolic disorders comprising obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, and hypertension [1,2]. Recent studies have demonstrated that the full activation of these receptors is associated with unwanted effects [5,6]. To overcome these issues, the concept of selective PPAR modulators (SPPARMs) with a superior balance of efficacy and safety has been proposed [7,8]

Methods

Results

Conclusion