N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer’s disease

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy Pub Date : 2025-09-27 DOI:10.1016/j.biopha.2025.118603

Óscar M. Bautista-Aguilera , Aleksandra Manik , Daniel Diez-Iriepa , Natalia Szałaj , Paula Zaręba , Anna Więckowska , Paweł Żmudzki , Ewelina Honkisz-Orzechowska , Damijan Knez , Stanislav Gobec , Kinga Sałat , Borja Martínez-Alonso , Víctor Guarnizo-Herrero , Guillermo Torrado Durán , Carlos Torrado-Salmerón , Aina Bellver-Sanchis , Inaya Nsiona-Defise , Marta Ribalta-Vilella , Mercè Pallàs , Francisco López-Muñoz , Isabel Iriepa

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引用次数: 0

Abstract

As part of a project aimed at the pharmacological optimization of Contilisant, herein we describe molecular modelling studies that led to the identification of MBA-159 as a new polyfunctionalized, multitarget-directed ligand and a promising drug candidate for the treatment of Alzheimer’s disease. We synthesized MBA-159 and conducted comprehensive in vitro and in vivo evaluations. In in vivo studies MBA-159 demonstrated favourable pharmacokinetics, anti-amnesic properties and significantly improved non-spatial memory (contextual and recognition memory) in a mouse model of scopolamine-induced amnesia. Additionally, MBA-159 showed a tendency to increase synaptic plasticity biomarkers and reduce neuroinflammatory trends (assessed by qPCR), as well as cognitive enhancement in a senescence-accelerated prone mouse 8 model.

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n-甲基- n-（（1-甲基-5-（3-（胡椒苷-1-基）丙氧基）- 1h -苯并咪唑-2-基）甲基）丙-2-氨基（MBA-159），一种新的治疗阿尔茨海默病的多靶点小分子

作为conconisant药理学优化项目的一部分，本文描述了分子模型研究，这些研究导致MBA-159被鉴定为一种新的多功能化、多靶点导向的配体和治疗阿尔茨海默病的有希望的候选药物。我们合成了MBA-159，并进行了全面的体外和体内评价。在体内研究中，MBA-159在东莨菪碱诱导的健忘症小鼠模型中表现出良好的药代动力学、抗遗忘特性和显著改善的非空间记忆（情境和识别记忆）。此外，MBA-159在衰老加速小鼠模型中显示出增加突触可塑性生物标志物和减少神经炎症趋势的趋势（通过qPCR评估），以及认知增强的趋势。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biomedicine & Pharmacotherapy 医学-药学

CiteScore

11.90

自引率

2.70%

发文量

1621

审稿时长

48 days

期刊介绍： Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.