Pharmaceutics (Sep 2023)

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

  • Andrea Bagán,
  • Sergio Rodriguez-Arévalo,
  • Teresa Taboada-Jara,
  • Christian Griñán-Ferré,
  • Mercè Pallàs,
  • Iria Brocos-Mosquera,
  • Luis F. Callado,
  • José A. Morales-García,
  • Belén Pérez,
  • Caridad Diaz,
  • Rosario Fernández-Godino,
  • Olga Genilloud,
  • Milan Beljkas,
  • Slavica Oljacic,
  • Katarina Nikolic,
  • Carmen Escolano

DOI
https://doi.org/10.3390/pharmaceutics15102381
Journal volume & issue
Vol. 15, no. 10
p. 2381

Abstract

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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.

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