Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease

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Abstract
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.
Funding Information
  • Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (PID2019-107991RB-I00, PID2022-139180OB-I00, PID2022-138079OB-I00, IT-1211-19, 1512-22, 2021 SGR 00357, PDC2022-133441-I00, MCIN/AEI/ 10.13039/501100011033, PR44/21-29931, No: 451-03-47/ 2023-01/200161)
  • Basque Government (PID2019-107991RB-I00, PID2022-139180OB-I00, PID2022-138079OB-I00, IT-1211-19, 1512-22, 2021 SGR 00357, PDC2022-133441-I00, MCIN/AEI/ 10.13039/501100011033, PR44/21-29931, No: 451-03-47/ 2023-01/200161)
  • Generalitat de Catalunya (PID2019-107991RB-I00, PID2022-139180OB-I00, PID2022-138079OB-I00, IT-1211-19, 1512-22, 2021 SGR 00357, PDC2022-133441-I00, MCIN/AEI/ 10.13039/501100011033, PR44/21-29931, No: 451-03-47/ 2023-01/200161)
  • European Union NextGenerationEU/PRTR (PID2019-107991RB-I00, PID2022-139180OB-I00, PID2022-138079OB-I00, IT-1211-19, 1512-22, 2021 SGR 00357, PDC2022-133441-I00, MCIN/AEI/ 10.13039/501100011033, PR44/21-29931, No: 451-03-47/ 2023-01/200161)
  • UCM-Santander (PID2019-107991RB-I00, PID2022-139180OB-I00, PID2022-138079OB-I00, IT-1211-19, 1512-22, 2021 SGR 00357, PDC2022-133441-I00, MCIN/AEI/ 10.13039/501100011033, PR44/21-29931, No: 451-03-47/ 2023-01/200161)
  • University of Belgrade—Faculty of Pharmacy (PID2019-107991RB-I00, PID2022-139180OB-I00, PID2022-138079OB-I00, IT-1211-19, 1512-22, 2021 SGR 00357, PDC2022-133441-I00, MCIN/AEI/ 10.13039/501100011033, PR44/21-29931, No: 451-03-47/ 2023-01/200161)

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