- Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT6 receptor antagonist with therapeutic interest in Alzheimer's disease
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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.
- Toublet, Fran?ois-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
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- Compound Having Oxadiazole And Pharmaceutical Composition Containing The Same
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Disclosed are oxadiazole compounds and pharmaceutically acceptable salts thereof. The compounds and pharmaceutically acceptable salts thereof are specifically suitable for the treatment of neurological diseases such as epilepsy.
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Paragraph 0170-0171
(2021/04/23)
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- Synthesis of Fluorinated Alkyl Aryl Ethers by Palladium-Catalyzed C-O Cross-Coupling
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Herein, we report a highly effective protocol for the cross-coupling of (hetero)aryl bromides with fluorinated alcohols using the commercially available precatalyst tBuBrettPhos Pd G3 and Cs2CO3 in toluene. This Pd-catalyzed coupling features a short reaction time, excellent functional group tolerance, and compatibility with electron-rich and-poor (hetero)arenes. The method provides access to 18F-labeled trifluoroethyl ethers by cross-coupling with [18F]trifluoroethanol.
- Szpera, Robert,Isenegger, Patrick G.,Ghosez, Maxime,Straathof, Natan J. W.,Cookson, Rosa,Blakemore, David C.,Richardson, Paul,Gouverneur, Véronique
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supporting information
p. 6573 - 6577
(2020/09/02)
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- Process for the Manufacture of Idalopirdine via Hydrogenation of an Imine
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The present invention relates to the preparation of N-(2-(6-fluoro-1H-indol-3-yl)-ethyl)-3-(2,2,3,3-tetrafluoropropoxy)-benzylamine (Compound I), INN-name idalopirdine, and pharmaceutically acceptable salts thereof:
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Paragraph 0127
(2017/10/27)
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- PROCESS FOR THE MANUFACTURE OF IDALOPIRDINE
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Disclosed herein is a process for the preparation of idalopirdine and pharmaceutically acceptable salts thereof.
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Paragraph 0099; 0101
(2016/07/05)
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