Dallemagne P

References (28)

Title : Biginelli Reaction Synthesis of Novel Multitarget-Directed Ligands with Ca(2+) Channel Blocking Ability, Cholinesterase Inhibition, Antioxidant Capacity, and Nrf2 Activation - Malek_2022_Molecules_28_
Author(s) : Malek R , Simakov A , Davis A , Maj M , Bernard PJ , Wnorowski A , Martin H , Marco-Contelles J , Chabchoub F , Dallemagne P , Rochais C , Jozwiak K , Ismaili L
Ref : Molecules , 28 : , 2022
Abstract : Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.
ESTHER : Malek_2022_Molecules_28_
PubMedSearch : Malek_2022_Molecules_28_
PubMedID: 36615267

Title : Advances in prodrug design for Alzheimer's disease: the state of the art - Travers-Lesage_2022_Expert.Opin.Drug.Discov_17_325
Author(s) : Travers-Lesage V , Mignani SM , Dallemagne P , Rochais C
Ref : Expert Opin Drug Discov , 17 :325 , 2022
Abstract : INTRODUCTION: Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease that remains today a challenge for drug discovery. Like many pathologies of the central nervous system, one of the first hurdle is the development of a compound with a sufficient brain exposure to ensure a potential therapeutic benefit. In this direction, the development of prodrugs has been an intense field of research in the last years. AREAS COVERED: Two main strategies of prodrugs development are analyzed in this review. First, the application of the classical modulation of an active compound to incorporate a promoiety has been exemplified in the field of AD. In a second chapter, a series of innovative prodrugs based on a polypharmacological approach is described to take into account the complexity of AD. EXPERT OPINION: In the past 10 years, prodrugs have been approved by the FDA for the treatment of CNS pathologies. Most of them have been developed in order to improve membrane permeability of the parent drugs. Facing the limitation of AD drug discovery, the development of prodrugs will likely play a central role in the next years with the rise of innovative pleiotropic prodrugs.
ESTHER : Travers-Lesage_2022_Expert.Opin.Drug.Discov_17_325
PubMedSearch : Travers-Lesage_2022_Expert.Opin.Drug.Discov_17_325
PubMedID: 35089846

Title : Active Targeted Nanoemulsions for Repurposing of Tegaserod in Alzheimer's Disease Treatment - Seguy_2021_Pharmaceutics_13_
Author(s) : Seguy L , Guyon L , Maurel M , Verdie P , Davis A , Corvaisier S , Lisowski V , Dallemagne P , Groo AC , Malzert-Freon A
Ref : Pharmaceutics , 13 : , 2021
Abstract : BACKGROUND AND PURPOSE: The activation of 5-HT(4) receptors with agonists has emerged as a valuable therapeutic strategy to treat Alzheimer's disease (AD) by enhancing the nonamyloidogenic pathway. Here, the potential therapeutic effects of tegaserod, an effective agent for irritable bowel syndrome, were assessed for AD treatment. To envisage its efficient repurposing, tegaserod-loaded nanoemulsions were developed and functionalized by a blood-brain barrier shuttle peptide. RESULTS: The butyrylcholinesterase inhibitory activity of tegaserod and its neuroprotective cellular effects were highlighted, confirming the interest of this pleiotropic drug for AD treatment. In regard to its drugability profile, and in order to limit its peripheral distribution after IV administration, its encapsulation into monodisperse lipid nanoemulsions (Tg-NEs) of about 50 nm, and with neutral zeta potential characteristics, was performed. The stability of the formulation in stock conditions at 4 degreesC and in blood biomimetic medium was established. The adsorption on Tg-NEs of peptide-22 was realized. The functionalized NEs were characterized by chromatographic methods (SEC and C(18)/HPLC) and isothermal titration calorimetry, attesting the efficiency of the adsorption. From in vitro assays, these nanocarriers appeared suitable for enabling tegaserod controlled release without hemolytic properties. CONCLUSION: The developed peptide-22 functionalized Tg-NEs appear as a valuable tool to allow exploration of the repurposed tegaserod in AD treatment in further preclinical studies.
ESTHER : Seguy_2021_Pharmaceutics_13_
PubMedSearch : Seguy_2021_Pharmaceutics_13_
PubMedID: 34683919

Title : Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer's Disease Treatment through Rigidification Strategy - Lecoutey_2021_Molecules_26_
Author(s) : Lecoutey C , Legay R , Davis A , Sopkova-de Oliveira Santos J , Dallemagne P , Rochais C
Ref : Molecules , 26 : , 2021
Abstract : 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(4) 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-HT(4)R and 5-HT(6)R and this study led to the description of novel ligand targeting both AChE and 5-HT(6)R.
ESTHER : Lecoutey_2021_Molecules_26_
PubMedSearch : Lecoutey_2021_Molecules_26_
PubMedID: 33926141

Title : Disproportionality analysis in VigiBase as a drug repositioning method for the discovery of potentially useful drugs in Alzheimer's disease - Chretien_2021_Br.J.Clin.Pharmacol_87_2830
Author(s) : Chretien B , Jourdan JP , Davis A , Fedrizzi S , Bureau R , Sassier M , Rochais C , Alexandre J , Lelong-Boulouard V , Dolladille C , Dallemagne P
Ref : British Journal of Clinical Pharmacology , 87 :2830 , 2021
Abstract : Drug repositioning aims to propose new indications for marketed drugs. Although several methods exist, the utility of pharmacovigilance databases for this purpose is unclear. We conducted a disproportionality analysis in the World Health Organization pharmacovigilance database VigiBase to identify potential anticholinesterase drug candidates for repositioning in Alzheimer's disease (AD). METHODS: Disproportionality analysis is a validated method for detecting significant associations between drugs and adverse events (AEs) in pharmacovigilance databases. We applied this approach in VigiBase to establish the safety profile displayed by the anticholinesterase drugs used in AD and searched the database for drugs with similar safety profiles. The detected drugs with potential activity against acetylcholinesterase and butyrylcholinesterases (BuChEs) were then evaluated to confirm their anticholinesterase potential. RESULTS: We identified 22 drugs with safety profiles similar to AD medicines. Among these drugs, 4 (clozapine, aripiprazole, sertraline and S-duloxetine) showed a human BuChE inhibition rate of over 70% at 10(-5) M. Their human BuChE half maximal inhibitory concentration values were compatible with clinical anticholinesterase action in humans at their normal doses. The most active human BuChE inhibitor in our study was S-duloxetine, with a half maximal inhibitory concentration of 1.2 microM. Combined with its ability to inhibit serotonin (5-HT) reuptake, the use of this drug could represent a novel multitarget directed ligand therapeutic strategy for AD. CONCLUSION: We identified 4 drugs with repositioning potential in AD using drug safety profiles derived from a pharmacovigilance database. This method could be useful for future drug repositioning efforts.
ESTHER : Chretien_2021_Br.J.Clin.Pharmacol_87_2830
PubMedSearch : Chretien_2021_Br.J.Clin.Pharmacol_87_2830
PubMedID: 33274491

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 : First Synthesis of Racemic Trans Propargylamino-Donepezil, a Pleiotrope Agent Able to Both Inhibit AChE and MAO-B, with Potential Interest against Alzheimer's Disease - Guieu_2020_Molecules_26_
Author(s) : Guieu B , Lecoutey C , Legay R , Davis A , Sopkova de Oliveira Santos J , Altomare CD , Catto M , Rochais C , Dallemagne P
Ref : Molecules , 26 : , 2020
Abstract : Alzheimer's disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC(50) = 0.4 microM) and (h)MAO-B (IC(50) = 6.4 microM).
ESTHER : Guieu_2020_Molecules_26_
PubMedSearch : Guieu_2020_Molecules_26_
PubMedID: 33375412

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 : Pharmacotechnical Development of a Nasal Drug Delivery Composite Nanosystem Intended for Alzheimer's Disease Treatment - Adnet_2020_Pharmaceutics_12_
Author(s) : Adnet T , Groo AC , Picard C , Davis A , Corvaisier S , Since M , Bounoure F , Rochais C , Pluart LL , Dallemagne P , Malzert-Freon A
Ref : Pharmaceutics , 12 : , 2020
Abstract : Direct nose-to-brain delivery has been raised as a non-invasive powerful strategy to deliver drugs to the brain bypassing the blood-brain barrier (BBB). This study aimed at preparing and characterizing an innovative composite formulation, associating the liposome and hydrogel approaches, suitable for intranasal administration. Thermosensitive gel formulations were obtained based on a mixture of two hydrophilic polymers (Poloxamer 407, P407 and Poloxamer 188, P188) for a controlled delivery through nasal route via liposomes of an active pharmaceutical ingredient (API) of potential interest for Alzheimer's disease. The osmolarity and the gelation temperature (T degrees sol-gel) of formulations, defined in a ternary diagram, were investigated by rheometry and visual determination. Regarding the issue of assays, a mixture composed of P407/P188 (15/1%, w/w) was selected for intranasal administration in terms of T degrees sol-gel and for the compatibility with the olfactory mucosal (280 +/- 20 mOsmol, pH 6). Liposomes of API were prepared by the thin film hydration method. Mucoadhesion studies were performed by using mucin disc, and they showed the good natural mucoadhesive characteristics of in situ gel formulations, which increased when liposomes were added. The study demonstrated successful pharmacotechnical development of a promising API-loaded liposomes in a thermosensitive hydrogel intended for nasal Alzheimer's disease treatment.
ESTHER : Adnet_2020_Pharmaceutics_12_
PubMedSearch : Adnet_2020_Pharmaceutics_12_
PubMedID: 32168767

Title : New piperazine multi-effect drugs prevent neurofibrillary degeneration and amyloid deposition, and preserve memory in animal models of Alzheimer's disease - Sergeant_2019_Neurobiol.Dis_129_217
Author(s) : Sergeant N , Vingtdeux V , Eddarkaoui S , Gay M , Evrard C , Le Fur N , Laurent C , Caillierez R , Obriot H , Larchanche PE , Farce A , Coevoet M , Carato P , Kouach M , Descat A , Dallemagne P , Buee-Scherrer V , Blum D , Hamdane M , Buee L , Melnyk P
Ref : Neurobiol Dis , 129 :217 , 2019
Abstract : Alzheimer's Disease is a devastating dementing disease involving amyloid deposits, neurofibrillary tangles, progressive and irreversible cognitive impairment. Today, only symptomatic drugs are available and therapeutic treatments, possibly acting at a multiscale level, are thus urgently needed. To that purpose, we designed multi-effects compounds by synthesizing drug candidates derived by substituting a novel N,N'-disubstituted piperazine anti-amyloid scaffold and adding acetylcholinesterase inhibition property. Two compounds were synthesized and evaluated. The most promising hybrid molecule reduces both the amyloid pathology and the Tau pathology as well as the memory impairments in a preclinical model of Alzheimer's disease. In vitro also, the compound reduces the phosphorylation of Tau and inhibits the release of Abeta peptides while preserving the processing of other metabolites of the amyloid precursor protein. We synthetized and tested the first drug capable of ameliorating both the amyloid and Tau pathology in animal models of AD as well as preventing the major brain lesions and associated memory impairments. This work paves the way for future compound medicines against both Alzheimer's-related brain lesions development and the associated cognitive impairments.
ESTHER : Sergeant_2019_Neurobiol.Dis_129_217
PubMedSearch : Sergeant_2019_Neurobiol.Dis_129_217
PubMedID: 30928644

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 : Novel multitarget-directed ligands targeting acetylcholinesterase and sigma1 receptors as lead compounds for treatment of Alzheimer's disease: Synthesis, evaluation, and structural characterization of their complexes with acetylcholinesterase - Lalut_2019_Eur.J.Med.Chem_162_234
Author(s) : Lalut J , Santoni G , Karila D , Lecoutey C , Davis A , Nachon F , Silman I , Sussman JL , Weik M , Maurice T , Dallemagne P , Rochais C
Ref : Eur Journal of Medicinal Chemistry , 162 :234 , 2019
Abstract : Pleiotropic intervention may be a requirement for effective limitation of the progression of multifactorial diseases such as Alzheimer's Disease. One approach to such intervention is to design a single chemical entity capable of acting on two or more targets of interest, which are accordingly known as Multi-Target Directed Ligands (MTDLs). We recently described donecopride, the first MTDL able to simultaneously inhibit acetylcholinesterase and act as an agonist of the 5-HT4 receptor, which displays promising activities in vivo. Pharmacomodulation of donecopride allowed us to develop a novel series of indole derivatives possessing interesting in vitro activities toward AChE and the sigma1 receptor. The crystal structures of complexes of the most promising compounds with Torpedo californica AChE were solved in order to further understand their mode of inhibition.
ESTHER : Lalut_2019_Eur.J.Med.Chem_162_234
PubMedSearch : Lalut_2019_Eur.J.Med.Chem_162_234
PubMedID: 30447434
Gene_locus related to this paper: torca-ACHE

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 : Synthesis and biological evaluation of pyrano[4,3-b][1]benzopyranone derivatives as monoamine oxidase and cholinesterase inhibitors - Lecoutey_2012_MedChemComm_3_627
Author(s) : Lecoutey C , Rochais C , Genest D , Butt-Gueulle S , Ballandonne C , Corvaisier S , Dulin F , Lepailleur A , Sopkova-de , Dallemagne P
Ref : Medchemcomm , 33 :627 , 2018
Abstract : The synthesis of novel pyrrolothienopyrazines has been achieved with the aim to bring together in a sole compound both AChE inhibitory effect and 5-HT4R agonist activity. These Multi-Target Directed Ligands might theoretically alleviate the cognitive deficit in Alzheimer disease by restoring the cholinergic activity and by promoting the non-amyloidogenic formation of sAPPa which seems detrimental to the amyloid aggregation. Some of the synthesized compounds bear for the first time these dual activities and compound 15b appears particularly potent towards both AChE and 5-HT4R targets with IC50 and Ki in nanomolar levels. Although these MTDL behave as 5-HT4R antagonists rather than agonists, these results appear hopeful concerning the design of further MTDL with therapeutic interest in AD treatment.
ESTHER : Lecoutey_2012_MedChemComm_3_627
PubMedSearch : Lecoutey_2012_MedChemComm_3_627

Title : Benzylphenylpyrrolizinones with Anti-amyloid and Radical Scavenging Effects, Potentially Useful in Alzheimer's Disease Treatment - Jourdan_2017_ChemMedChem_12_913
Author(s) : Jourdan JP , Since M , El Kihel L , Lecoutey C , Corvaisier S , Legay R , Sopkova-de Oliveira Santos J , Cresteil T , Malzert-Freon A , Rochais C , Dallemagne P
Ref : ChemMedChem , 12 :913 , 2017
Abstract : Herein we describe the drug design steps developed to increase the radical scavenging and beta-amyloid aggregation inhibitory activities of a previously described series of benzylidenephenylpyrrolizinones. Among the newly synthesized derivatives, some benzylphenylpyrrolizinones exhibited interesting results in regard to those activities. Initial druggability parameters were measured, and suggest these compounds as a suitable starting point for potential alternatives in treating Alzheimer's disease.
ESTHER : Jourdan_2017_ChemMedChem_12_913
PubMedSearch : Jourdan_2017_ChemMedChem_12_913
PubMedID: 28342294

Title : Modulating 5-HT4 and 5-HT6 receptors in Alzheimer's disease treatment - Lalut_2017_Future.Med.Chem_9_781
Author(s) : Lalut J , Karila D , Dallemagne P , Rochais C
Ref : Future Med Chem , 9 :781 , 2017
Abstract : Alzheimer's disease (AD) is the most common form of dementia affecting millions of patients worldwide which can only be treated with symptomatic drugs. Among the numbers of biological targets which are today explored in order to prevent or limit the progression of AD, the modulation of 5-HT6R and 5-HT4R appeared to be promising. This modulation has been proved to enhance the cognition in AD through modulation of the neurotransmitter system but could also be beneficial in order to limit the amyloid pathology. This review will describe recent advances in the understanding of this modulation as well as the medicinal chemistry of 5-HT6R or 5-HT4R ligands from synthesis to ongoing clinical trials.
ESTHER : Lalut_2017_Future.Med.Chem_9_781
PubMedSearch : Lalut_2017_Future.Med.Chem_9_781
PubMedID: 28504917

Title : Design, synthesis, and pharmacological evaluation of multitarget-directed ligands with both serotonergic subtype 4 receptor (5-HT4R) partial agonist and 5-HT6R antagonist activities, as potential treatment of Alzheimer's disease - Yahiaoui_2016_Eur.J.Med.Chem_121_283
Author(s) : Yahiaoui S , Hamidouche K , Ballandonne C , Davis A , de Oliveira Santos JS , Freret T , Boulouard M , Rochais C , Dallemagne P
Ref : Eur Journal of Medicinal Chemistry , 121 :283 , 2016
Abstract : 5-HT4 receptor (5-HT4R) activation and blockade of the 5-HT6 receptor (5-HT6R) are known to enhance the release of numerous neurotransmitters whose depletion is implicated in Alzheimer's disease (AD). Furthermore, 5-HT4R agonists seem to favor production of the neurotrophic soluble amyloid protein precursor alpha (sAPPalpha). Consequently, combining 5-HT4R agonist/5-HT6R antagonist activities in a single chemical compound would constitute a novel approach able to display both a symptomatic and disease-modifying effect in AD. Seventeen novel derivatives of RS67333 (1) were synthesized and evaluated as potential dual-target compounds. Among them, four agents showed nanomolar and submicromolar affinities toward 5-HT4R and 5-HT6R, respectively; one of them, 7m, was selected on the basis of its in vitro affinity (Ki5-HT4R = 5.3 nM, Ki5-HT6R = 219 nM) for further in vivo experiments, where 7m showed an antiamnesic effect in the mouse at 1 mg/kg ip.
ESTHER : Yahiaoui_2016_Eur.J.Med.Chem_121_283
PubMedSearch : Yahiaoui_2016_Eur.J.Med.Chem_121_283
PubMedID: 27266998

Title : Novel benzylidenephenylpyrrolizinones with pleiotropic activities potentially useful in Alzheimer's disease treatment - Jourdan_2016_Eur.J.Med.Chem_114_365
Author(s) : Jourdan JP , Since M , El Kihel L , Lecoutey C , Corvaisier S , Legay R , Sopkova-de Oliveira Santos J , Cresteil T , Malzert-Freon A , Rochais C , Dallemagne P
Ref : Eur Journal of Medicinal Chemistry , 114 :365 , 2016
Abstract : This work describes the synthesis and the biological evaluation of novel benzylidenephenylpyrrolizinones as potential antioxidant, metal chelating or amyloid beta (betaA) aggregation inhibitors. Some derivatives exhibited interesting results in regard to several of the performed evaluations and appear as valuable Multi-Target Directed Ligands with potential therapeutic interest in Alzheimer's disease. Among them, compound 29 particularly appears as a valuable radical and NO scavenger, a Cu(II) and Fe(II) chelating agent and exhibits moderate betaA aggregation inhibition properties. These activities, associated to a good predictive bioavailability and a lack of cytotoxicity, design it as a promising hit for further in vivo investigation.
ESTHER : Jourdan_2016_Eur.J.Med.Chem_114_365
PubMedSearch : Jourdan_2016_Eur.J.Med.Chem_114_365
PubMedID: 27046230

Title : Synthesis and evaluation of novel serotonin 4 receptor radiotracers for single photon emission computed tomography - Lalut_2016_Eur.J.Med.Chem_116_90
Author(s) : Lalut J , Tournier BB , Cailly T , Lecoutey C , Corvaisier S , Davis A , Ballandonne C , Since M , Millet P , Fabis F , Dallemagne P , Rochais C
Ref : Eur Journal of Medicinal Chemistry , 116 :90 , 2016
Abstract : Despite its implication in several physiological and pathological processes the serotonin subtype-4 receptor (5-HT4R) has seen limited effort for the development of radiolabeling agent especially concerning single photon emission computed tomography (SPECT). Bearing an ester function, the available ligands are rapidly susceptible to hydrolysis which limits their use in vivo. In this study the synthesis of iodinated benzamide and ketone analogs were described. Their affinity for the 5-HT4R and their lipophilicity were evaluated and the most promising derivatives were evaluated ex vivo for their binding to the receptor and for their ability to displace the reference ligand [(125)I]-SB207710.
ESTHER : Lalut_2016_Eur.J.Med.Chem_116_90
PubMedSearch : Lalut_2016_Eur.J.Med.Chem_116_90
PubMedID: 27060761

Title : Therapeutic Potential of 5-HT6 Receptor Agonists - Karila_2015_J.Med.Chem_58_7901
Author(s) : Karila D , Freret T , Bouet V , Boulouard M , Dallemagne P , Rochais C
Ref : Journal of Medicinal Chemistry , 58 :7901 , 2015
Abstract : Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer's disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox.
ESTHER : Karila_2015_J.Med.Chem_58_7901
PubMedSearch : Karila_2015_J.Med.Chem_58_7901
PubMedID: 26099069

Title : Chronic activation of 5-HT4 receptors or blockade of 5-HT6 receptors improve memory performances - Quiedeville_2015_Behav.Brain.Res_293_10
Author(s) : Quiedeville A , Boulouard M , Hamidouche K , Da Silva Costa-Aze V , Nee G , Rochais C , Dallemagne P , Fabis F , Freret T , Bouet V
Ref : Behavioural Brain Research , 293 :10 , 2015
Abstract : 5-HT4 and 5-HT6 serotonergic receptors are located in brain structures involved in memory processes. Neurochemical and behavioural studies have demonstrated that acute activation of 5-HT4 receptors (5-HT4R) or blockade of 5-HT6 receptors (5-HT6R) improves memory. To evaluate the potential of these two receptors as targets in the treatment of memory disorders encountered in several situations (ageing, Alzheimer's disease, schizophrenia, etc.), it is necessary to assess whether their beneficial effects occur after chronic administration, and if such treatment induces adverse effects. The goal of this study was to assess the effects of chronic 5-HT4R or 5-HT6R modulation on recognition memory, and to observe the possible manifestation of side effects (modification of weight gain, locomotor activity or exploratory behaviour, etc.). Mice were treated for 14 days with a 5-HT4R partial agonist (RS-67333) or a 5-HT6R antagonist (SB-271046) at increasing doses. Memory performances, locomotor activity, and exploration were assessed. Both chronic 5-HT4R activation and 5-HT6R blockade extended memory traces in an object recognition test, and were not associated with any adverse effects in the parameters assessed. Chronic modulation of one or both of these receptors thus seems promising as a potential strategy for the treatment memory deficits.
ESTHER : Quiedeville_2015_Behav.Brain.Res_293_10
PubMedSearch : Quiedeville_2015_Behav.Brain.Res_293_10
PubMedID: 26187692

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

Title : Synergistic effect of acetylcholinesterase inhibition (donepezil) and 5-HT(4) receptor activation (RS67333) on object recognition in mice - Freret_2012_Behav.Brain.Res_230_304
Author(s) : Freret T , Bouet V , Quiedeville A , Nee G , Dallemagne P , Rochais C , Boulouard M
Ref : Behavioural Brain Research , 230 :304 , 2012
Abstract : Facing inefficiency of current treatments to cure Alzheimer disease (AD), a pharmacological approach is now emerging on the assumption that a single compound may be able to hit multiple targets, namely Multi-Target-Directed Ligands (MTDLs). Displaying numerous advantages, several MTDL for AD have been recently described but none associating an inhibition of AChE and an activation of 5-HT(4)R. The aim of this study was to validate the concept of a synergistic action of these two targets on episodic-like memory performances in mice. Among potent molecules, RS67333, a reference 5-HT(4)R agonist and donepezil (DNPZ), a reference acetylcholinesterase inhibitor, have been particularly chosen because of their close chemical structure. Administered separately, RS67333 (0.3 and 1mg/kg) and DNPZ (1mg/kg) improved recognition performances compared to saline treated animals but not with lower doses. Co-administration of subactive doses of RS67333 (0.1mg/kg) and DNPZ (0.3mg/kg) improved memory, moreover, this improvement is prevented if a 5-HT(4)R antagonist (GR125487, 10mg/kg) is also administered. Activation of 5-HT(4)R combined with inhibition of AChE with subactive doses of RS67333 and of DNPZ has synergistic effects on memory performances in mice. These molecules having close chemical structures, the synergistic effect of their combination affords new hope to chemist for the synthesis of MTDL.
ESTHER : Freret_2012_Behav.Brain.Res_230_304
PubMedSearch : Freret_2012_Behav.Brain.Res_230_304
PubMedID: 22348892

Title : Virtual screening discovery of new acetylcholinesterase inhibitors issued from CERMN chemical library - Sopkova-de_2010_J.Chem.Inf.Model_50_422
Author(s) : Sopkova-de Oliveira Santos J , Lesnard A , Agondanou JH , Dupont N , Godard AM , Stiebing S , Rochais C , Fabis F , Dallemagne P , Bureau R , Rault S
Ref : J Chem Inf Model , 50 :422 , 2010
Abstract : In our quest to find new inhibitors able to inhibit acetylcholinesterase (AChE) and, at the same time, to protect neurons from beta amyloid toxicity, i.e., inhibitors interacting with the catalytic anionic subsite as well as with the peripherical anionic site of AChE, a virtual screening of the Centre d'Etudes et de Recherche sur le Medicament de Normandie (CERMN) chemical library was carried out. Two complementary approaches were applied, i.e., a ligand- and a structure-based screening. Each screening led to the selection of different compounds, but only two were present in both screening results. In vitro tests on AChE showed that one of those compounds presented a very good inhibition activity, of the same order as Donepezil. This result shows the real complementary of both methods for the discovery of new ligands.
ESTHER : Sopkova-de_2010_J.Chem.Inf.Model_50_422
PubMedSearch : Sopkova-de_2010_J.Chem.Inf.Model_50_422
PubMedID: 20196555

Title : Synthesis and preliminary in vivo evaluation of new 2-Aryl-6-methyl-1,2-dihydro-1H-pyridin-4-ones and 2-Aryl-6-methylpiperidin-4-ols, as potential anti-amnesiant agents - Leflemme_2005_J.Enzyme.Inhib.Med.Chem_20_551
Author(s) : Leflemme N , Freret T , Boulouard M , Dallemagne P , Rault S
Ref : J Enzyme Inhib Med Chem , 20 :551 , 2005
Abstract : A revisited synthesis of 2-aryl-6-methyl-1,2-dihydro-1H-pyridin-4-ones and their saturated analogues 2-aryl-6-methylpiperidin-4-ols is described. A five steps procedure, using the sulfinimine chemistry, to prepare a key intermediate beta-(6-chloronicotinic)-beta-amino ester is also reported. In vivo spontaneous working memory activity of these compounds has been investigated in the mouse. Results obtained with 2-(3-chlorophenyl)-6-methyl-1,2-dihydro-1H-pyridin-4-one 9b, the most effective derivative in this model, have been reported.
ESTHER : Leflemme_2005_J.Enzyme.Inhib.Med.Chem_20_551
PubMedSearch : Leflemme_2005_J.Enzyme.Inhib.Med.Chem_20_551
PubMedID: 16408790

Title : Synthesis and biological evaluation as AChE inhibitors of new indanones and thiaindanones related to donepezil - Omran_2005_Eur.J.Med.Chem_40_1222
Author(s) : Omran Z , Cailly T , Lescot E , Santos JS , Agondanou JH , Lisowski V , Fabis F , Godard AM , Stiebing S , Le Flem G , Boulouard M , Dauphin F , Dallemagne P , Rault S
Ref : Eur Journal of Medicinal Chemistry , 40 :1222 , 2005
Abstract : Sixty-four new indanones and thiaindanones related to donepezil were synthesized and evaluated in vitro as potential AChE inhibitors. Among them, 11 derivatives were found to inhibit the enzyme in the submicromolar range; the best compound revealed its inhibitory activity with an IC50 in the same range (0.06 microM) than the reference compound, donepezil (IC50=0.02 microM).
ESTHER : Omran_2005_Eur.J.Med.Chem_40_1222
PubMedSearch : Omran_2005_Eur.J.Med.Chem_40_1222
PubMedID: 16137794