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

• Published in: European journal of medicinal chemistry Vol. 210; pp. 113059 - 113072
• Main Authors: Toublet, François-Xavier, Lalut, Julien, Hatat, Bérénice, Lecoutey, Cédric, Davis, Audrey, Since, Marc, Corvaisier, Sophie, Freret, Thomas, Sopková-de Oliveira Santos, Jana, Claeysen, Sylvie, Boulouard, Michel, Dallemagne, Patrick, Rochais, Christophe
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.01.2021; Elsevier
• Subjects: 5-HT6 receptors; Alzheimer’s disease; Butyrylcholinesterase; Chemical Sciences; Chemistry, Medicinal; Life Sciences; Life Sciences & Biomedicine; Medicinal Chemistry; MTDL; Neurobiology; Neurons and Cognition; Pharmacology & Pharmacy; Prodrugs; Science & Technology; CCDC; rt; BBB; DMSO; ACh; You can provide MOL files of the most relevant compounds discussed in your paper when you return the corrections. Click here for more information. For information on how to create MOL files please see here; MTDL; cAMP; CPZ; SC; OPTIONAL; HRMS; CHX; THF; BuChE; Pe; IC50; SCOP; DMF; LSD; HPLC; PBS; AChE; ChE; Prodrugs; AD; Alzheimer’s disease; DTNB; 5-HT6 receptors; IP; PAMPA; Butyrylcholinesterase; ACN; BuChEI; EDTA; DCM; LD50; 5-HTxR; LC-MS; MAO; MK801; 5-HT; Ki; TARGET-DIRECTED LIGANDS; VALIDATION; IDALOPIRDINE; GENETIC ALGORITHM; STRATEGIES; OBJECT RECOGNITION; FORCE-FIELD; SEROTONIN; SIMULATIONS; CHARMM; Alzheimer's disease; 5-HT receptors
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.113059

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 μM). The latter will deliver after hydrolysis, compound 6, a potent 5-HT6 receptors antagonist (Ki = 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. [Display omitted] •Idalopirdine analogue was prepared to include a carbamate moiety.•The carbamate analogue is a pseudo-irreversible BuChE inhibitor.•After decarbamoylation the prodrug generates a potent 5-HT6R antagonist.•In vivo studies confirmed the potential of this pleiotropic prodrug strategy.