Lecoutey Cédric, Legay Rémi, Davis Audrey, Sopková-de Oliveira Santos Jana, Dallemagne Patrick, Rochais Christophe
Normandie Univ, Unicaen, Cermn, 14000 Caen, France.
Molecules. 2021 Apr 26;26(9):2536. doi: 10.3390/molecules26092536.
The development of Multi-Target Directed Ligand is of clear interest for the treatment of multifactorial pathology such as Alzheimer's disease (AD). In this context, acetylcholinesterase (AChE) inhibitors have been modulated in order to generate novel pleiotropic compounds targeting a second protein of therapeutic interest in AD. Among them, donecopride was the first example of a dual acetylcholinesterase inhibitor and 5-HT receptor agonist. In order to explore the structural diversity around this preclinical candidate we have explored the preparation of novel constrained analogs through late-stage rigidification strategy. A series of phenylpyrazoles was prepared in a late-stage functionalization process and all compounds were evaluated in vitro towards AChE and 5-HTRs. A docking study was performed in order to better explain the observed SAR towards AChE, 5-HTR and 5-HTR and this study led to the description of novel ligand targeting both AChE and 5-HTR.
多靶点导向配体的研发对于治疗诸如阿尔茨海默病（AD）等多因素病理状况显然具有重要意义。在此背景下，乙酰胆碱酯酶（AChE）抑制剂已得到调控，以生成针对AD中另一种具有治疗意义的蛋白质的新型多效性化合物。其中，多奈哌齐是双乙酰胆碱酯酶抑制剂和5-羟色胺受体激动剂的首个实例。为了探索围绕这一临床前候选药物的结构多样性，我们通过后期刚性化策略研究了新型受限类似物的制备。在后期功能化过程中制备了一系列苯基吡唑，并对所有化合物进行了针对AChE和5-羟色胺受体（5-HTRs）的体外评估。进行了对接研究，以便更好地解释观察到的针对AChE、5-HTR和5-HTR的构效关系（SAR），该研究促成了对同时靶向AChE和5-HTR的新型配体的描述。
