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Tau-Centric Multitarget Approach for Alzheimer's Disease: Development of First-in-Class Dual Glycogen Synthase Kinase 3β and Tau-Aggregation Inhibitors

AuthorsGandini, A.; Bartolini, M.; Tedesco, D.; Martínez-González, Loreto CSIC ORCID ; Roca, Carlos; Campillo, Nuria E. CSIC ORCID ; Zaldívar-Díez, Josefa; Pérez, Concepción; Zuccheri, G.; Miti, A.; Feoli, A.; Castellano, S.; Petralla, S.; Monti, B.; Rossi, M.; Moda, F.; Legname, G.; Martínez, Ana; Bolognesi, Maria Laura
Issue Date2018
PublisherAmerican Chemical Society
CitationJournal of Medicinal Chemistry 61: 7640-7656 (2018)
AbstractSeveral findings propose the altered tau protein network as an important target for Alzheimer's disease (AD). Particularly, two points of pharmacological intervention can be envisaged: inhibition of phosphorylating tau kinase GSK-3β and tau aggregation process. On the basis of this consideration and on our interest in multitarget paradigms in AD, we report on the discovery of 2,4-thiazolidinedione derivatives endowed with such a profile. 28 and 30 displayed micromolar IC values toward GSK-3β, together with the capacity of inhibiting AcPHF6 aggregation of 60% and 80% at 10 μM, respectively. In addition, they showed PAMPA-BBB permeability, together with a suitable cellular safety profile. 30 also displayed inhibition of both K18 and full-length tau aggregations. Finally, both compounds were able to improve cell viability in an okadaic acid-induced neurodegeneration cell model. To the best of our knowledge, 28 and 30 are the first balanced, nontoxic, dual-acting compounds hitting tau cascade at two different hubs.
Publisher version (URL)http://dx.doi.org/10.1021/acs.jmedchem.8b00610
Identifiersdoi: 10.1021/acs.jmedchem.8b00610
issn: 0022-2623
e-issn: 1520-4804
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