Marco-Contelles José, Unzeta Mercedes, Bolea Irene, Esteban Gerard, Ramsay Rona R, Romero Alejandro, Martínez-Murillo Ricard, Carreiras M Carmo, Ismaili Lhassane
Laboratory of Medicinal Chemistry, Institute of General Organic Chemistry, Cajal Institute (CSIC) Madrid, Spain.
Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Institut de Neurociències, Universitat Autònoma de Barcelona Barcelona, Spain.
Front Neurosci. 2016 Jun 28;10:294. doi: 10.3389/fnins.2016.00294. eCollection 2016.
ASS2324 is a hybrid compound resulting from the juxtaposition of donepezil and the propargylamine PF9601N ASS2324 is a multi-target directed propargylamine able to bind to all the AChE/BuChE and MAO A/B enzymesASS2324 shows antioxidant, neuroprotective and suitable permeability propertiesASS2324 restores the scopolamine-induced cognitive impairment to the same extent as donepezil, and is less toxicASS2324 prevents β-amyloid induced aggregation in the cortex of double transgenic miceASS2324 is the most advanced anti-Alzheimer agent for pre-clinical studies that we have identified in our laboratories The complex nature of Alzheimer's disease (AD) has prompted the design of Multi-Target-Directed Ligands (MTDL) able to bind to diverse biochemical targets involved in the progress and development of the disease. In this context, we have designed a number of MTD propargylamines (MTDP) showing antioxidant, anti-beta-amyloid, anti-inflammatory, as well as cholinesterase and monoamine oxidase (MAO) inhibition capacities. Here, we describe these properties in the MTDL ASS234, our lead-compound ready to enter in pre-clinical studies for AD, as a new multipotent, permeable cholinesterase/monoamine oxidase inhibitor, able to inhibit Aβ-aggregation, and possessing antioxidant and neuroprotective properties.
ASS2324是一种由多奈哌齐与炔丙胺PF9601N并列组合而成的杂合化合物。ASS2324是一种多靶点导向的炔丙胺，能够与所有的乙酰胆碱酯酶/丁酰胆碱酯酶以及单胺氧化酶A/B结合。ASS2324具有抗氧化、神经保护以及合适的通透性特性。ASS2324能将东莨菪碱诱导的认知障碍恢复到与多奈哌齐相同的程度，且毒性更小。ASS2324可防止β-淀粉样蛋白在双转基因小鼠皮质中诱导聚集。ASS2324是我们在实验室中鉴定出的用于临床前研究的最先进的抗阿尔茨海默病药物。阿尔茨海默病（AD）的复杂性促使人们设计出能够与该疾病进展和发展过程中涉及的多种生化靶点结合的多靶点导向配体（MTDL）。在此背景下，我们设计了多种具有抗氧化、抗β-淀粉样蛋白、抗炎以及胆碱酯酶和单胺氧化酶（MAO）抑制能力的MTD炔丙胺（MTDP）。在此，我们将我们准备进入AD临床前研究的先导化合物MTDL ASS234描述为一种新型的多效、可渗透的胆碱酯酶/单胺氧化酶抑制剂，它能够抑制Aβ聚集，并具有抗氧化和神经保护特性。
