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ACS Chem Neurosci ; 13(15): 2252-2260, 2022 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-35868251

RESUMEN

Polypharmacology is a new trend in amyotrophic lateral sclerosis (ALS) therapy and an effective way of addressing a multifactorial etiology involving excitotoxicity, mitochondrial dysfunction, oxidative stress, and microglial activation. Inspired by a reported clinical trial, we converted a riluzole (1)-rasagiline (2) combination into single-molecule multi-target-directed ligands. By a ligand-based approach, the highly structurally integrated hybrids 3-8 were designed and synthesized. Through a target- and phenotypic-based screening pipeline, we identified hit compound 6. It showed monoamine oxidase A (MAO-A) inhibitory activity (IC50 = 6.9 µM) rationalized by in silico studies as well as in vitro brain permeability. By using neuronal and non-neuronal cell models, including ALS-patient-derived cells, we disclosed for 6 a neuroprotective/neuroinflammatory profile similar to that of the parent compounds and their combination. Furthermore, the unexpected MAO inhibitory activity of 1 (IC50 = 8.7 µM) might add a piece to the puzzle of its anti-ALS molecular profile.


Asunto(s)
Esclerosis Amiotrófica Lateral , Fármacos Neuroprotectores , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Humanos , Indanos , Ligandos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Riluzol/farmacología , Riluzol/uso terapéutico
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