Bagán, AndreaMorales García, José ÁngelEscolano, Carmen2024-11-182024-11-182023-09-25Bagán, 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/pharmaceutics1510238110.3390/pharmaceutics15102381https://hdl.handle.net/20.500.14352/1106802023 Descuento MDPIHumanity 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.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal article1999-4923https://doi.org/10.3390/pharmaceutics1510238137896141https://www.mdpi.com/1999-4923/15/10/2381https://pubmed.ncbi.nlm.nih.gov/37896141/open access616.894-053.9Imidazoline I2 receptor ligandAlzheimer’s diseaseImidazoline-linked heterocycle2-(benzo[b]thiophen-2-yl)-1H-imidazole5XFAD3D-QSARNeuroprotectionMedicinaBiología celular (Biología)32 Ciencias Médicas2407 Biología Celular