RT Journal Article
T1 Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease
A1 Bagán, Andrea
A1 Morales García, José Ángel
A1 Escolano, Carmen
AB Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer’s disease (AD) being the most dominant, without efficacious drugs, and with only a few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I2 receptors (I2-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I2-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature. We report the synthesis, the affinity in human I2-IRs, the brain penetration capabilities, the in silico ADMET studies, and the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of this new bunch of I2-IR ligands. Selected compounds showed neuroprotective properties and beneficial effects in an in vitro model of Parkinson’s disease, rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine, and showed crucial anti-inflammatory effects in a cellular model of neuroinflammation. After a preliminary pharmacokinetic study, we explored the action of our representative 2-(benzo[b]thiophen-2-yl)-1H-imidazole LSL33 in a mouse model of AD (5xFAD). Oral administration of LSL33 at 2 mg/Kg for 4 weeks ameliorated 5XFAD cognitive impairment and synaptic plasticity, as well as reduced neuroinflammation markers. In summary, this new I2-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration.
PB MDPI
YR 2023
FD 2023-09-25
LK https://hdl.handle.net/20.500.14352/110680
UL https://hdl.handle.net/20.500.14352/110680
LA eng
NO Bagán, A.; RodriguezArévalo, S.; Taboada-Jara, T.; Griñán-Ferré, C.; Pallàs, M.; Brocos-Mosquera, I.; Callado, L.F.; Morales-García, J.A.; Pérez, B.; Diaz, C.; et al. Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease. Pharmaceutics 2023, 15, 2381. https://doi.org/10.3390/pharmaceutics15102381
NO 2023 Descuento MDPI
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO European Commission
NO Gobierno Vasco
NO Generalitat de Catalunya
NO Universidad Complutense de Madrid
NO Banco Santander
DS Docta Complutense
RD 12 abr 2025