Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT6 receptor antagonist with therapeutic interest in Alzheimer's disease

Beside acetylcholinesterase, butyrylcholinesterase could be considered as a putative target of interest for the symptomatic treatment of Alzheimer's disease (AD). As a result of complexity of AD, no molecule has been approved since 2002. Idalopirdine, a 5-HT6 receptors antagonist, did not show its effectiveness in clinical trial despite its evaluation as adjunct to cholinesterase inhibitors. Pleiotropic molecules, known as multitarget directed ligands (MTDLs) are currently developed to tackle the multifactorial origin of AD. In this context, we have developed a pleiotropic carbamate 7, that behaves as a covalent inhibitor of BuChE (IC50 = 0.97 mM). The latter will deliver after hydrolysis, compound 6, a potent 5-HT6 receptors antagonist (K-i = 11.4 nM) related to idalopirdine. In silico and in vitro evaluation proving our concept were performed completed with first in vivo results that demonstrate great promise in restoring working memory. (C) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

Novel multitarget directed ligands are being developed in the field of Alzheimer's disease treatment to address the complexity of the disease. In this context, a new pleiotropic carbamate has been developed as a covalent inhibitor of BuChE and a precursor to a potent 5-HT6 receptors antagonist, showing promising in silico and in vitro results as well as first in vivo findings in restoring working memory.