Claeysen S

References (7)

Title : Donecopride, a Swiss army knife with potential against Alzheimer's disease - Rochais_2020_Br.J.Pharmacol_177_1988
Author(s) : Rochais C , Lecoutey C , Hamidouche K , Giannoni P , Gaven F , Cem E , Mignani S , Baranger K , Freret T , Bockaert J , Rivera S , Boulouard M , Dallemagne P , Claeysen S
Ref : British Journal of Pharmacology , 177 :1988 , 2020
Abstract : BACKGROUND AND PURPOSE: We recently identified donecopride as a pleiotropic compound able to inhibit AChE and to activate 5-HT4 receptors. Here, we have assessed the potential therapeutic effects of donecopride in treating Alzheimer's disease (AD). EXPERIMENTAL APPROACH: We used two in vivo animal models of AD, transgenic 5XFAD mice and mice exposed to soluble amyloid-beta peptides and, in vitro, primary cultures of rat hippocampal neurons. Pro-cognitive and anti-amnesic effects were evaluated with novel object recognition, Y-maze, and Morris water maze tests. Amyloid load in mouse brain was measured ex vivo and effects of soluble amyloid-beta peptides on neuronal survival and neurite formation determined in vitro. KEY RESULTS: In vivo, chronic (3 months) administration of donecopride displayed potent anti-amnesic properties in the two mouse models of AD, preserving learning capacities, including working and long-term spatial memories. These behavioural effects were accompanied by decreased amyloid aggregation in the brain of 5XFAD mice and, in cultures of rat hippocampal neurons, reduced tau hyperphosphorylation. In vitro, donecopride increased survival in neuronal cultures exposed to soluble amyloid-beta peptides, improved the neurite network and provided neurotrophic benefits, expressed as the formation of new synapses. CONCLUSIONS AND IMPLICATIONS: Donecopride acts like a Swiss army knife, exhibiting a range of sustainable symptomatic therapeutic effects and potential disease-modifying effects in models of AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans.
ESTHER : Rochais_2020_Br.J.Pharmacol_177_1988
PubMedSearch : Rochais_2020_Br.J.Pharmacol_177_1988
PubMedID: 31881553

Title : Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT4 receptors activities for the treatment of Alzheimer's disease - Lalut_2020_Sci.Rep_10_3014
Author(s) : Lalut J , Payan H , Davis A , Lecoutey C , Legay R , Sopkova-de Oliveira Santos J , Claeysen S , Dallemagne P , Rochais C
Ref : Sci Rep , 10 :3014 , 2020
Abstract : A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HT4R agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget directed ligands. The chemical synthesis of the ligand was optimized and compounds were evaluated in vitro against each target and in cellulo. Structure-activity relationship was supported by docking analysis in human acetylcholinesterase binding site. Among the synthesized compounds, we have identified a novel hybrid 32a (3-[2-[1-(cyclohexylmethyl)-4-piperidyl]ethyl]-4-methoxy-1,2-benzoxazole) able to display nanomolar acetylcholinesterase inhibitory effects and nanomolar Ki for 5-HT4R.
ESTHER : Lalut_2020_Sci.Rep_10_3014
PubMedSearch : Lalut_2020_Sci.Rep_10_3014
PubMedID: 32080261

Title : Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT(6) receptor antagonist with therapeutic interest in Alzheimer's disease - Toublet_2020_Eur.J.Med.Chem_210_113059
Author(s) : Toublet FX , Lalut J , Hatat B , Lecoutey C , Davis A , Since M , Corvaisier S , Freret T , Sopkova-de Oliveira Santos J , Claeysen S , Boulouard M , Dallemagne P , Rochais C
Ref : Eur Journal of Medicinal Chemistry , 210 :113059 , 2020
Abstract : 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-HT(6) 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 (IC(50) = 0.97 M). The latter will deliver after hydrolysis, compound 6, a potent 5-HT(6) 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.
ESTHER : Toublet_2020_Eur.J.Med.Chem_210_113059
PubMedSearch : Toublet_2020_Eur.J.Med.Chem_210_113059
PubMedID: 33310288

Title : Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer's Disease - Toublet_2019_Molecules_24_
Author(s) : Toublet FX , Lecoutey C , Lalut J , Hatat B , Davis A , Since M , Corvaisier S , Freret T , Sopkova de Oliveira Santos J , Claeysen S , Boulouard M , Dallemagne P , Rochais C
Ref : Molecules , 24 : , 2019
Abstract : Alzheimer's disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.
ESTHER : Toublet_2019_Molecules_24_
PubMedSearch : Toublet_2019_Molecules_24_
PubMedID: 31370232

Title : A Novel in vivo Anti-amnesic Agent, Specially Designed to Express Both Acetylcholinesterase (AChE) Inhibitory, Serotonergic Subtype 4 Receptor (5-HT4R) Agonist and Serotonergic Subtype 6 Receptor (5-HT6R) Inverse Agonist Activities, With a Potential Interest Against Alzheimer's Disease - Hatat_2019_Front.Aging.Neurosci_11_148
Author(s) : Hatat B , Yahiaoui S , Lecoutey C , Davis A , Freret T , Boulouard M , Claeysen S , Rochais C , Dallemagne P
Ref : Front Aging Neurosci , 11 :148 , 2019
Abstract : This work describes the conception, synthesis, in vitro and in vivo biological evaluation of novel Multi-Target Directed Ligands (MTDL) able to both activate 5-HT4 receptors, block 5-HT6 receptors and inhibit acetylcholinesterase activity (AChE), in order to exert a synergistic anti-amnesic effect, potentially useful in the treatment of Alzheimer's disease (AD). Indeed, both activation of 5-HT4 and blockage of 5-HT6 receptors led to an enhanced acetylcholine release, suggesting it could lead to efficiently restoring the cholinergic neurotransmission deficit observed in AD. Furthermore, 5-HT4 receptor agonists are able to promote the non-amyloidogenic cleavage of the amyloid precursor protein (APP) and to favor the production of the neurotrophic protein sAPPalpha. Finally, we identified a pleiotropic compound, [1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-(3-methylbenzyl)piperidin-4-yl)propan- 1-one fumaric acid salt (10)], which displayed in vivo an anti-amnesic effect in a model of scopolamine-induced deficit of working memory at a dose of 0.3 mg/kg.
ESTHER : Hatat_2019_Front.Aging.Neurosci_11_148
PubMedSearch : Hatat_2019_Front.Aging.Neurosci_11_148
PubMedID: 31316368

Title : Novel multitarget-directed ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HT4R) agonist activities as potential agents against Alzheimer's disease: the design of donecopride - Rochais_2015_J.Med.Chem_58_3172
Author(s) : Rochais C , Lecoutey C , Gaven F , Giannoni P , Hamidouche K , Hedou D , Dubost E , Genest D , Yahiaoui S , Freret T , Bouet V , Dauphin F , Sopkova de Oliveira Santos J , Ballandonne C , Corvaisier S , Malzert-Freon A , Legay R , Boulouard M , Claeysen S , Dallemagne P
Ref : Journal of Medicinal Chemistry , 58 :3172 , 2015
Abstract : In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPalpha release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer's disease.
ESTHER : Rochais_2015_J.Med.Chem_58_3172
PubMedSearch : Rochais_2015_J.Med.Chem_58_3172
PubMedID: 25793650

Title : Design of donecopride, a dual serotonin subtype 4 receptor agonist\/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment - Lecoutey_2014_Proc.Natl.Acad.Sci.U.S.A_111_E3825
Author(s) : Lecoutey C , Hedou D , Freret T , Giannoni P , Gaven F , Since M , Bouet V , Ballandonne C , Corvaisier S , Malzert Freon A , Mignani S , Cresteil T , Boulouard M , Claeysen S , Rochais C , Dallemagne P
Ref : Proc Natl Acad Sci U S A , 111 :E3825 , 2014
Abstract : RS67333 is a partial serotonin subtype 4 receptor (5-HT4R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-beta peptide leads to the secretion of the neurotrophic protein sAPPalpha. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer's disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitarget-directed ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT4R partial agonist (Ki = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC50 = 16 nM) that further promotes sAPPalpha release (EC50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.
ESTHER : Lecoutey_2014_Proc.Natl.Acad.Sci.U.S.A_111_E3825
PubMedSearch : Lecoutey_2014_Proc.Natl.Acad.Sci.U.S.A_111_E3825
PubMedID: 25157130