Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer's Disease
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 I<sub>2&l...
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Main Authors: | , , , , , , , , , , , , , , , |
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Format: | Book |
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MDPI AG,
2023-09-01T00:00:00Z.
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Summary: | 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 I<sub>2</sub> receptors (I<sub>2</sub>-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I<sub>2</sub>-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature. We report the synthesis, the affinity in human I<sub>2</sub>-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 I<sub>2</sub>-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[<i>b</i>]thiophen-2-yl)-1<i>H</i>-imidazole <b>LSL33</b> in a mouse model of AD (5xFAD). Oral administration of <b>LSL33</b> at 2 mg/Kg for 4 weeks ameliorated 5XFAD cognitive impairment and synaptic plasticity, as well as reduced neuroinflammation markers. In summary, this new I<sub>2</sub>-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration. |
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Item Description: | 10.3390/pharmaceutics15102381 1999-4923 |