Title
Tau-Centric Multitarget Approach for Alzheimer’s Disease: Development of First-in-Class Dual Glycogen Synthase Kinase 3β and Tau-Aggregation Inhibitors
Author
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
Year
2018
Journal
Journal of Medicinal Chemistry
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.
Instrument
J-810
Keywords
Circular dichroism, Secondary structure, Chemical stability, Medicinal, Biochemistry