Delving into the Latest Updates on Contilisant with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

Cholinesterase x H3 receptor x MAO x σ1 receptor

Mechanism

Cholinesterase inhibitors, H3 receptor antagonists(Histamine H3 receptor antagonists), MAO inhibitors(Monoamine oxidase inhibitors)

+ [1]

Therapeutic Areas

Nervous System Diseases

Active Indication

Alzheimer Disease

Inactive Indication-

Originator Organization

Consejo Superior de Investigaciones Científicas

Active Organization

Consejo Superior de Investigaciones Científicas

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Paricio, Nuria ; Schäker-Hübner, Linda ; Iriepa, Isabel ; Mora-Morell, Alba ; Dong, Min ; Knez, Damijan ; Rodrìguez, Ania Canseco ; Więckowska, Anna ; Griñán-Ferré, Christian ; Dobrydnev, Alexey V. ; Hansen, Finn K. ; Romero, Fernando ; Satała, Grzegorz ; Sànchez-Pérez, Ana M ; Matheu, Ander ; Gobec, Stanislav ; Handzlik, Jadwiga ; Bautista-Aguilera, Òscar M. ; Sanchis, Inmaculada ; Porro-Pérez, Alicia ; Godyń, Justyna ; Marco-Contelles, José ; Solana-Manrique, Cristina ; Almendros, Pedro ; Toledano-Pinedo, Mireia ; Rodríguez-Fernández, M. Mercedes ; Bojarski, Andrzej J. ; Doroz-Płonka, Agata ; Pérez, Belén ; Artetxe-Zurutuza, Aizpea ; Bellver-Sanchis, Aina ; Wolak, Małgorzata ; Samadi, Abdelouahid ; Siwek, Agata

Herein, we describe the design, synthesis, and biological evaluation of 15 Contilisant+Tubastatin A hybrids. These ligands are polyfunctionalized indole derivatives developed by juxtaposing selected pharmacophoric moieties of Contilisant and Tubastatin A to act as multifunctional ligands. Compounds 3 and 4 were identified as potent HDAC6 inhibitors (IC₅₀ = 0.012 μM and 0.035 μM, respectively), so they were further evaluated in Drosophila and human cell models of Parkinson's disease (PD). Both compounds attenuated PD-like phenotypes, such as motor defects, oxidative stress, and mitochondrial dysfunction in PD model flies. Ligands 3 and 4 were also studied in the transgenic Caenorhabditis elegans CL2006 model of Alzheimer's disease (AD). Both compounds were nontoxic, did not induce undesirable animal functional changes, inhibited age-related paralysis, and improved cognition in the thrashing assay. These results highlight 3 and 4 as novel multifunctional ligands that improve the features of PD and AD hallmarks in the respective animal models.

100 Deals associated with Contilisant

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