Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy
Copyright policy )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 of therapeutic interest in AD. Among them, donecopride was the first example of a dual acetylcholinesterase inhibitor and 5-HT4 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-HT4R and 5-HT6R and this study led to the description of novel ligand targeting both AChE and 5-HT6R.
- Université de Caen Normandie France
- University of Caen Lower Normandy France
- Normandie Université France
Molecular Conformation, Organic chemistry, Chemistry Techniques, Synthetic, Molecular Dynamics Simulation, Ligands, MTDL, Article, Structure-Activity Relationship, QD241-441, Drug Development, 615, 616, [CHIM]Chemical Sciences, Humans, 5-HT<sub>6</sub>R, Binding Sites, donecopride, Hydrogen Bonding, acetylcholinesterase, Molecular Docking Simulation, Acetylcholinesterase, Cholinesterase Inhibitors, Alzheimer’s disease, Protein Binding
Molecular Conformation, Organic chemistry, Chemistry Techniques, Synthetic, Molecular Dynamics Simulation, Ligands, MTDL, Article, Structure-Activity Relationship, QD241-441, Drug Development, 615, 616, [CHIM]Chemical Sciences, Humans, 5-HT<sub>6</sub>R, Binding Sites, donecopride, Hydrogen Bonding, acetylcholinesterase, Molecular Docking Simulation, Acetylcholinesterase, Cholinesterase Inhibitors, Alzheimer’s disease, Protein Binding
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