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Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy
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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123621/ https://www.ncbi.nlm.nih.gov/pubmed/33926141 http://dx.doi.org/10.3390/molecules26092536 |
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author | Lecoutey, Cédric Legay, Rémi Davis, Audrey Sopková-de Oliveira Santos, Jana Dallemagne, Patrick Rochais, Christophe |
author_facet | Lecoutey, Cédric Legay, Rémi Davis, Audrey Sopková-de Oliveira Santos, Jana Dallemagne, Patrick Rochais, Christophe |
author_sort | Lecoutey, Cédric |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8123621 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81236212021-05-16 Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy Lecoutey, Cédric Legay, Rémi Davis, Audrey Sopková-de Oliveira Santos, Jana Dallemagne, Patrick Rochais, Christophe Molecules Article 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. MDPI 2021-04-26 /pmc/articles/PMC8123621/ /pubmed/33926141 http://dx.doi.org/10.3390/molecules26092536 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lecoutey, Cédric Legay, Rémi Davis, Audrey Sopková-de Oliveira Santos, Jana Dallemagne, Patrick Rochais, Christophe Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy |
title | Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy |
title_full | Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy |
title_fullStr | Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy |
title_full_unstemmed | Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy |
title_short | Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy |
title_sort | development of novel potential pleiotropic compounds of interest in alzheimer’s disease treatment through rigidification strategy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123621/ https://www.ncbi.nlm.nih.gov/pubmed/33926141 http://dx.doi.org/10.3390/molecules26092536 |
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