From the Dual Function Lead AP2238 to AP2469, a Multi-target-directed Ligand for the Treatment of Alzheimer's Disease

Overview

Journal Pharmacol Res Perspect

Date 2014 Dec 16

PMID 25505579

Citations 18

Authors

Andrea Tarozzi

Manuela Bartolini

Lorna Piazzi

Luca Valgimigli

Riccardo Amorati

Cecilia Bolondi

Alice Djemil

Francesca Mancini

Vincenza Andrisano

Angela Rampa

Affiliations

Soon will be listed here.

Abstract

The development of drugs with different pharmacological properties appears to be an innovative therapeutic approach for Alzheimer's disease. In this article, we describe a simple structural modification of AP2238, a first dual function lead, in particular the introduction of the catechol moiety performed in order to search for multi-target ligands. The new compound AP2469 retains anti-acetylcholinesterase (AChE) and beta-site amyloid precursor protein cleaving enzyme (BACE)1 activities compared to the reference, and is also able to inhibit Aβ 42 self-aggregation, Aβ 42 oligomer-binding to cell membrane and subsequently reactive oxygen species formation in both neuronal and microglial cells. The ability of AP2469 to interfere with Aβ 42 oligomer-binding to neuron and microglial cell membrane gives this molecule both neuroprotective and anti-inflammatory properties. These findings, together with its strong chain-breaking antioxidant performance, make AP2469 a potential drug able to modify the course of the disease.

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