Multitarget drug discovery for Alzheimer's disease: triazinones as BACE-1 and GSK-3β inhibitors
Open accessAbstract
Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer's disease (AD). Thus, the development of multitarget drugs which are involved in both pathways might represent a promising therapeutic strategy. Accordingly, reported here in is the discovery of 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as the first class of molecules able to simultaneously modulate BACE-1 and GSK-3β. Notably, one triazinone showed well-balanced in vitro potencies against the two enzymes (IC50 of (18.03±0.01) μM and (14.67±0.78) μM for BACE-1 and GSK-3β, respectively). In cell-based assays, it displayed effective neuroprotective and neurogenic activities and no neurotoxicity. It also showed good brain permeability in a preliminary pharmacokinetic assessment in mice. Overall, triazinones might represent a promising starting point towards high quality lead compounds with an AD-modifying potential.
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BACE-1 and GSK-3β inhibition are being studied as possible targets for Alzheimer's disease.
“Nowadays, other possible targets are being studied, such as beta-secretase 1 (BACE-1) and glycogen synthase kinase-3β (GSK-3β) inhibition (De Simone et al., 2021;Prati et al., 2015).”
From Multi-target neuroprotective effects of herbal medicines for Alzheimer's disease (2022) · cites this paper as Prati et al., 2015
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Cites
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864 · see citing works
Microtubule-associated protein tau. A component of Alzheimer paired helical filaments.
Grundke, I., Iqbal, K., Quinlan, M., Tung, Y. C., Zaidi, M. S., & Wisniewski, H. M. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)38495-8 · Cited by 1,780 · see citing works
Amyloid-β and tau — a toxic pas de deux in Alzheimer's disease
Ittner, L. M., & Götz, J. (2010) · Nature reviews. Neuroscience · doi:10.1038/nrn2967 · Cited by 1,357 · see citing works
Multi-target-Directed Ligands To Combat Neurodegenerative Diseases
Cavalli, A., Bolognesi, M. L., Minarini, A., Rosini, M., Tumiatti, V., Recanatini, M., & Melchiorre, C. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm7009364 · Cited by 1,152 · see citing works
Self-citationReview: Activation patterns of microglia and their identification in the human brain
Boche, D., Perry, V. H., & Nicoll, J. A. R. (2012) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12011 · Cited by 911 · see citing works
Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery
Hann, M. M., Leach, A. R., & Harper, G. (2001) · Journal of Chemical Information and Computer Sciences · doi:10.1021/ci000403i · Cited by 882 · see citing works
Hutchinson, E. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn2985 · Cited by 534 · see citing works
GSK-3β, a pivotal kinase in Alzheimer disease
Llorens-MarÃtin, M., Jurado, J., Hernández, F., & Ãvila, J. (2014) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2014.00046 · Cited by 451 · see citing works
Neuroinflammation: Modulation by flavonoids and mechanisms of action
Spencer, J. P. E., Vafeiadou, K., Williams, R. J., & Vauzour, D. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2011.10.016 · Cited by 315 · see citing works
Vassar, R. J., & Citron, M. (2000) · Neuron · doi:10.1016/s0896-6273(00)00051-9 · Cited by 299 · see citing works
Yuskaitis, C. J., & Jope, R. S. (2009) · Cellular Signalling · doi:10.1016/j.cellsig.2008.10.014 · Cited by 240 · see citing works
Fragments, network biology and designing multiple ligands
Morphy, R., & Ranković, Z. (2006) · Drug Discovery Today · doi:10.1016/j.drudis.2006.12.006 · Cited by 204 · see citing works
Viayna, E., Sola, I., Bartolini, M., Simone, A. D., Tapia‐Rojas, C., Serrano, F. G., Sabaté, R., Juárez‐Jiménez, J., Pérez, B., Luque, F. J., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401824w · Cited by 156 · see citing works
Self-citationÁvila, J., Wandosell, F. G., & Hernández, F. (2010) · Expert Review of Neurotherapeutics · doi:10.1586/ern.10.40 · Cited by 135 · see citing works
A High Throughput Luminescent Assay for Glycogen Synthase Kinase-3 β Inhibitors
Baki, A., Bielik, A., Molnár, L. M., Szendrei, G. I., & Keserű, G. M. (2007) · Assay and Drug Development Technologies · doi:10.1089/adt.2006.029 · Cited by 126 · see citing works
From Single Target to Multitarget/Network Therapeutics in Alzheimer’s Therapy
Zheng, H., Fridkin, M., & Youdim, M. B. H. (2014) · Pharmaceuticals · doi:10.3390/ph7020113 · Cited by 119 · see citing works
The role of fragment-based and computational methods in polypharmacology
Bottegoni, G., Favia, A. D., Recanatini, M., & Cavalli, A. (2011) · Drug Discovery Today · doi:10.1016/j.drudis.2011.08.002 · Cited by 116 · see citing works
Self-citationSmall molecule GSK-3 inhibitors increase neurogenesis of human neural progenitor cells
Lange, C. M., Mix, E., Frahm, J., Glass, A. S., Müller, J. A., Schmitt, O., Schmöle, A., Klemm, K., Ortinau, S., Hübner, R., et al. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.10.076 · Cited by 100 · see citing works
Neuroprotection by the selective iNOS inhibitor GW274150 in a model of Parkinson disease
Broom, L., Marinova-Mutafchieva, L., Sadeghian, M., Davis, J. B., Medhurst, A. D., & Dexter, D. T. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.12.026 · Cited by 96 · see citing works
Mancini, F., Simone, A. D., & Andrisano, V. (2011) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-011-4963-x · Cited by 96 · see citing works
Self-citationPalomo, V., Pérez, D. I., Pérez, C., Morales-Garcia, J. A., Soteras, I., Alonso‐Gil, S., Encinas, A., Castro, A., Campillo, N. E., Pérez‐Castillo, A., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm201463v · Cited by 93 · see citing works
Neuronal-glial Interactions Define the Role of Nitric Oxide in Neural Functional Processes
Contestabile, A., Monti, B., & Polazzi, E. (2012) · Current Neuropharmacology · doi:10.2174/157015912804143522 · Cited by 45 · see citing works
Self-citationAn effective treatment for Alzheimer's disease must consider both amyloid and tau
Lansdall, C. J. (2014) · Bioscience Horizons The International Journal of Student Research · doi:10.1093/biohorizons/hzu002 · Cited by 45 · see citing works
Lessons Learnt from Glycogen Synthase Kinase 3 Inhibitors Development for Alzheimer’s Disease
Martı́nez, A., Pérez, D. I., & Gil, C. (2013) · Current Topics in Medicinal Chemistry · doi:10.2174/15680266113139990138 · Cited by 33 · see citing works
Neuronal-glial Interactions Define the Role of Nitric Oxide in Neural Functional Processes
Contestabile, A., Monti, B., & Polazzi, E. (2012) · Current Neuropharmacology · doi:10.2174/157015912804499465 · Cited by 27 · see citing works
Self-citationSimone, A. D., Ruda, G. F., Albani, C., Tarozzo, G., Bandiera, T., Piomelli, D., Cavalli, A., & Bottegoni, G. (2014) · Chemical Communications · doi:10.1039/c4cc00967c · Cited by 25 · see citing works
Self-citation(2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4273 · Cited by 4 · see citing works
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Chalupova, K., Korabecny, J., Bartolini, M., Monti, B., Lamba, D., Caliandro, R., Pesaresi, A., Brazzolotto, X., Gastellier, A.-J., Nachon, F., et al. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.02.021 · Cited by 118 · see citing works
Self-citationPrati, F., Cavalli, A., & Bolognesi, M. (2016) · Molecules · doi:10.3390/molecules21040466 · Cited by 110 · see citing works
Self-citationDe Simone, A., Tumiatti, V., Andrisano, V., & Milelli, A. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00931 · Cited by 110 · see citing works
Self-citationGonzález, J. F., Alcántara, A. R., Doadrio, A. L., & Sánchez-Montero, J. M. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1623201 · Cited by 98 · see citing works
Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy
Zagórska, A., & Jaromin, A. (2020) · Molecules · doi:10.3390/molecules25153337 · Cited by 51 · see citing works
Multi-target neuroprotective effects of herbal medicines for Alzheimer's disease
Fernandes, F., Barroso, M. F., De Simone, A., Emriková, E., Dias-Teixeira, M., Pereira, J. P., Chlebek, J., Fernandes, V. C., Rodrigues, F., Andrisano, V., et al. (2022) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2022.115107 · Cited by 45 · see citing works
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- Authors
- Prati, F., De Simone, A., Bisignano, P., Armirotti, A., Summa, M., Pizzirani, D., Scarpelli, R., Perez, D. I., Andrisano, V., Perez‐Castillo, A., Monti, B., Massenzio, F., Polito, L., Racchi, M., Favia, A. D., Bottegoni, G., Martinez, A., Bolognesi, M. L., & Cavalli, A.
- Affiliations
- Italian Institute of Technology (IT)
- University of Bologna (IT)
- Fondazione Golgi Cenci (IT)
- University of Pavia (IT)
- Corresponding author
- Cavalli, Andrea
- ORCID
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2014-12-11
- Volume
- 54
- Issue
- 5
- Pages
- 1578-1582
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- OpenAlex
- W2107330191
- Cited by
- 128
- References
- 27
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 12 · 2023: 10 · 2022: 9 · 2021: 6 · 2020: 14 · 2019: 19 · 2018: 17 · 2017: 16 · 2016: 11 · 2015: 9
- FWCI
- 8.64
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Università di Bologna
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
- Keywords
- Alzheimer's disease, multi-target drug discovery, triazinones, BACE1 inhibitors, GSK-3β inhibitors, amyloid hypothesis, tau hypothesis, neuroprotection, neurogenesis, brain permeability, lead compounds
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Animals, Blood-Brain Barrier, Drug Evaluation, Preclinical, Enzyme Inhibitors, Half-Life, Lipopolysaccharides, Protein Binding, Triazines, Drug Design, Up-Regulation, Aspartic Acid Endopeptidases, Microglia, Catalytic Domain, Glycogen Synthase Kinase 3, Mice, Rats, Nitric Oxide Synthase Type II, Amyloid Precursor Protein Secretases, Molecular Docking Simulation
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