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Title: Benzofuranyl-2-imidazoles as imidazoline I2 receptor ligands for Alzheimer's disease
Author: Rodríguez-Arévalo, Sergio
Bagan Polonio, Andrea
Griñán Ferré, Christian
Vasilopoulou, Foteini
Pallàs i Llibería, Mercè, 1964-
Brocos-Mosquera, Iria
Callado, Luis F.
Loza, María Isabel
Martínez, Antón L.
Brea, José
Pérez, Belén
Molins i Grau, Elies
Jonghe, Steven de
Daelemans, Dirk
Radan, Milica
Djikic, Teodora
Nikolic, Katarina
Hernández-Hernández, Elena
García-Fuster, M. Julia
García-Sevilla, Jesús A.
Escolano Mirón, Carmen
Keywords: Malaltia d'Alzheimer
Malalties neurodegeneratives
Alzheimer's disease
Neurodegenerative Diseases
Issue Date: 22-Jun-2021
Publisher: Elsevier Masson SAS
Abstract: Recent findings unveil the pharmacological modulation of imidazoline I2 receptors (I2-IR) as a novel strategy to face unmet medical neurodegenerative diseases. In this work, we report the chemical characterization, three-dimensional quantitative structure-activity relationship (3D-QSAR) and ADMET in silico of a family of benzofuranyl-2-imidazoles that exhibit affinity against human brain I2-IR and most of them have been predicted to be brain permeable. Acute treatment in mice with 2-(2-benzofuranyl)-2- imidazole, known as LSL60101 (garsevil), showed non-warning properties in the ADMET studies and an optimal pharmacokinetic profile. Moreover, LSL60101 induced hypothermia in mice while decreased pro-apoptotic FADD protein in the hippocampus. In vivo studies in the familial Alzheimer's disease 5xFAD murine model with the representative compound, revealed significant decreases in the protein expression levels of antioxidant enzymes superoxide dismutase and glutathione peroxidase in hippocampus. Overall, LSL60101 plays a neuroprotective role by reducing apoptosis and modulating oxidative stress.
Note: Versió postprint del document publicat a:
It is part of: European Journal of Medicinal Chemistry, 2021, vol. 222, p. 113540
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ISSN: 0223-5234
Appears in Collections:Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)

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