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

• Main Authors: Andrea Bagán (Author), Sergio Rodriguez-Arévalo (Author), Teresa Taboada-Jara (Author), Christian Griñán-Ferré (Author), Mercè Pallàs (Author), Iria Brocos-Mosquera (Author), Luis F. Callado (Author), José A. Morales-García (Author), Belén Pérez (Author), Caridad Diaz (Author), Rosario Fernández-Godino (Author), Olga Genilloud (Author), Milan Beljkas (Author), Slavica Oljacic (Author), Katarina Nikolic (Author), Carmen Escolano (Author)
• Format: Book
• Published: MDPI AG, 2023-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/pharmaceutics15102381; 1999-4923
• Keywords: imidazoline I₂ receptor ligand; Alzheimer's disease; imidazoline-linked heterocycle; 2-(benzo[<i>b</i>]thiophen-2-yl)-1<i>H</i>-imidazole; 5XFAD; 3D-QSAR; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutics, Vol 15, Iss 10, p 2381 (2023)

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[<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 I₂-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration.