Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease
Authors
Bagán, AndreaRodriguez-Arévalo, Sergio
Taboada-Jara, Teresa
Griñán-Ferré, Christian
Pallàs, Mercè
Brocos-Mosquera, Iria
Callado, Luis F.
Morales-García, José A.
Pérez, Belén
Diaz, Caridad
Fernández-Godino, Rosario
Genilloud, Olga
Beljkaš, Milan
Oljačić, Slavica
Nikolić, Katarina
Escolano, Carmen
Article (Published version)
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Show full item recordAbstract
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, a...nd 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.
Keywords:
Alzheimer’s disease / 2-(benzo[b]thiophen-2-yl)-1H-imidazole / 3D-QSAR / 5XFAD / imidazoline I2 receptor ligand / imidazoline-linked heterocycle / neuroprotectionSource:
Pharmaceutics, 2023, 15, 10Publisher:
- MDPI
Funding / projects:
- The Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (Spain, PID2019-107991RB-I00, PID2022-139180OB-I00, PID2022- 138079OB-I00))
- Basque Government (IT-1211-19 and 1512-22
- Generalitat de Catalunya (GC) (2021 SGR 00357) and PDC2022-133441-I00 (MCIN/AEI/ 10.13039/501100011033)
- The European Union NextGenerationEU/PRTR) and UCM-Santander (PR44/21-29931 to J.A.M.-G.).
- Razvoj i primena proizvoda na bazi mineralnih sirovina u proizvodnji bezbedne hrane (RS-MESTD-MPN2006-2010-20016)
DOI: 10.3390/pharmaceutics15102381
ISSN: 1999-4923
WoS: 37896141
Scopus: 2-s2.0-85175042972
Collections
Institution/Community
PharmacyTY - JOUR AU - Bagán, Andrea AU - Rodriguez-Arévalo, Sergio AU - Taboada-Jara, Teresa AU - Griñán-Ferré, Christian AU - Pallàs, Mercè AU - Brocos-Mosquera, Iria AU - Callado, Luis F. AU - Morales-García, José A. AU - Pérez, Belén AU - Diaz, Caridad AU - Fernández-Godino, Rosario AU - Genilloud, Olga AU - Beljkaš, Milan AU - Oljačić, Slavica AU - Nikolić, Katarina AU - Escolano, Carmen PY - 2023 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5206 AB - 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. PB - MDPI T2 - Pharmaceutics T1 - Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease VL - 15 IS - 10 DO - 10.3390/pharmaceutics15102381 ER -
@article{ author = "Bagán, Andrea and Rodriguez-Arévalo, Sergio and Taboada-Jara, Teresa and Griñán-Ferré, Christian and Pallàs, Mercè and Brocos-Mosquera, Iria and Callado, Luis F. and Morales-García, José A. and Pérez, Belén and Diaz, Caridad and Fernández-Godino, Rosario and Genilloud, Olga and Beljkaš, Milan and Oljačić, Slavica and Nikolić, Katarina and Escolano, Carmen", year = "2023", 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.", publisher = "MDPI", journal = "Pharmaceutics", title = "Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease", volume = "15", number = "10", doi = "10.3390/pharmaceutics15102381" }
Bagán, A., Rodriguez-Arévalo, S., Taboada-Jara, T., Griñán-Ferré, C., Pallàs, M., Brocos-Mosquera, I., Callado, L. F., Morales-García, J. A., Pérez, B., Diaz, C., Fernández-Godino, R., Genilloud, O., Beljkaš, M., Oljačić, S., Nikolić, K.,& Escolano, C.. (2023). Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease. in Pharmaceutics MDPI., 15(10). https://doi.org/10.3390/pharmaceutics15102381
Bagán A, Rodriguez-Arévalo S, Taboada-Jara T, Griñán-Ferré C, Pallàs M, Brocos-Mosquera I, Callado LF, Morales-García JA, Pérez B, Diaz C, Fernández-Godino R, Genilloud O, Beljkaš M, Oljačić S, Nikolić K, Escolano C. Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease. in Pharmaceutics. 2023;15(10). doi:10.3390/pharmaceutics15102381 .
Bagán, Andrea, Rodriguez-Arévalo, Sergio, Taboada-Jara, Teresa, Griñán-Ferré, Christian, Pallàs, Mercè, Brocos-Mosquera, Iria, Callado, Luis F., Morales-García, José A., Pérez, Belén, Diaz, Caridad, Fernández-Godino, Rosario, Genilloud, Olga, Beljkaš, Milan, Oljačić, Slavica, Nikolić, Katarina, Escolano, Carmen, "Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease" in Pharmaceutics, 15, no. 10 (2023), https://doi.org/10.3390/pharmaceutics15102381 . .