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

Annachiara Gandini, Manuela Bartolini, Daniele Tedesco, Loreto Martinez-Gonzalez, Carlos Roca, Nuria E. Campillo, Josefa Zaldivar-Diez, Concepción Perez, Giampaolo Zuccheri, Andrea Miti, Alessandra Feoli, Sabrina Castellano, Sabrina Petralla, Barbara Monti, Martina Rossi, Fabio Moda, Giuseppe Legname, Ana Martinez, Maria Laura Bolognesi

Research output: Contribution to journalArticle

Abstract

Several 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 IC50 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.

Original languageEnglish
Pages (from-to)7640-7656
Number of pages17
JournalJournal of Medicinal Chemistry
Volume61
Issue number17
DOIs
Publication statusPublished - Sep 13 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Gandini, A., Bartolini, M., Tedesco, D., Martinez-Gonzalez, L., Roca, C., Campillo, N. E., Zaldivar-Diez, J., Perez, C., Zuccheri, G., Miti, A., Feoli, A., Castellano, S., Petralla, S., Monti, B., Rossi, M., Moda, F., Legname, G., Martinez, A., & Bolognesi, M. L. (2018). Tau-Centric Multitarget Approach for Alzheimer's Disease: Development of First-in-Class Dual Glycogen Synthase Kinase 3β and Tau-Aggregation Inhibitors. Journal of Medicinal Chemistry, 61(17), 7640-7656. https://doi.org/10.1021/acs.jmedchem.8b00610