New flurbiprofen derivatives: synthesis, membrane affinity and evaluation of in vitro effect on β-amyloid levels.

Piera Sozio,Amelia Cataldi,Antonella Fontana,Lucia Grumetto,Hasan Türkez,Gianfabio Giorgioni,Antonio Di Stefano,Dario Ambrosini,Francesco Barbato,Stephanie Pacella,Ivana Cacciatore,Lisa Marinelli

doi:10.3390/molecules180910747

Abstract

Alzheimer’s disease (AD) is characterized by irreversible and progressive loss of memory and cognition and profound neuronal loss. Current therapeutic strategies for the treatment of AD have been directed to a variety of targets with the aim of reversing or preventing the disease but, unfortunately, the available treatments often produce no significant clinical benefits. During the last decades compounds that inhibit or modulate γ-secretase, reducing β amyloid (Aβ) levels, have been considered as potential therapeutics for AD. Among these the (R)-enantiomer of flurbiprofen (FLU) seems to be very promising, but it shows low brain penetration. In this study, in order to improve the properties of FLU against Alzheimer’s pathogenesis we synthesized some novel FLU lipophilic analogues. Lipophilicity of the new molecules has been characterized in terms of clogP, log KC18/W and log K IAM/W values. Permeability has been determined in both gastrointestinal PAMPA (PAMPA-GI) at different pH values and in brain blood barrier PAMPA (PAMPA-BBB) models. They were also tested for their ability to inhibit in vitro γ-secretase activity using rat CTXTNA2 astrocytes. Interestingly, the investigated molecules demonstrated to reduce Aβ 42 levels without affecting the amyloid precursor protein APP level in a clear concentrations-dependent manner.

Highlights

Alzheimer’s disease (AD) is one of the most common types of dementia, characterized by irreversible and progressive loss of memory and cognition and profound neuronal loss [1]
Compounds 1–3 were synthesized as outlined in Scheme 1 by using stepwise elongation of the peptide chain in the C-to-N direction via standard solution phase procedures
Our results show that there is a broadly agreement between clogP and logKIAM/W data

Summary

Introduction

Alzheimer’s disease (AD) is one of the most common types of dementia, characterized by irreversible and progressive loss of memory and cognition and profound neuronal loss [1]. Current therapeutic strategies for the treatment of AD have been directed to a variety of targets with the aim of reversing or preventing the disease but, the available treatments produce limited clinical benefits [2]. During the last decades many investigations have been directed to the modulation of amyloid precursor protein (APP) transcription, including α-, β-, and γ-secretase. Compounds that inhibit or modulate γ-secretase can be considered as a potential therapeutics for AD because their use appears to be a rational strategy to prevent senile plaque (SP) formations [3]. When administered in mice they inhibit APP cleavage, dose dependently reducing β amyloid (Aβ) levels and avoiding plaque formation [4].The major problem associated with these inhibitors is their non selective targeting towards APP. As a matter of fact they inhibit the cleavage of the Notch receptor, causing embryological defects, interferences in B and T lymphocytes proliferation, and abnormalities in the gastrointestinal (GI) tract [5,6]

Methods

Results

Conclusion