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

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.