2024-03-28T21:42:10Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1777302022-12-28T11:05:06Zcom_10261_81com_10261_5com_10261_86com_10261_1col_10261_334col_10261_339
00925njm 22002777a 4500
dc
Gandini, A.
author
Bartolini, M.
author
Tedesco, D.
author
Martínez-González, Loreto
author
Roca, Carlos
author
Campillo, Nuria E.
author
Zaldívar-Díez, Josefa
author
Pérez, Concepción
author
Zuccheri, G.
author
Miti, Andrea
author
Feoli, A.
author
Castellano, S.
author
Petralla, S.
author
Monti, B.
author
Rossi, M.
author
Moda, F.
author
Legname, G.
author
Martínez, Ana
author
Bolognesi, Maria Laura
author
2018
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 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.
Journal of Medicinal Chemistry 61: 7640-7656 (2018)
http://hdl.handle.net/10261/177730
10.1021/acs.jmedchem.8b00610
http://dx.doi.org/10.13039/100008914
http://dx.doi.org/10.13039/501100002283
http://dx.doi.org/10.13039/501100003196
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100005969
Tau-Centric Multitarget Approach for Alzheimer's Disease: Development of First-in-Class Dual Glycogen Synthase Kinase 3β and Tau-Aggregation Inhibitors