Published August 4, 2018 | Version accepted_manuscript
Journal article Open

Tau-centric multi-target approach for Alzheimer's disease: Development of first-in-class glycogen synthase kinase 3β and tau-aggregation inhibitors

Creators

  • 1. University of Bologna, Italy; International School for Advanced Studies, Italy
  • 2. University of Bologna, Italy
  • 3. CSIC, Spain
  • 4. University of Bologna, Italy; National Research Council, Italy
  • 5. University of Salerno, Italy
  • 6. nternational School for Advanced Studies, Italy
  • 7. IRCCS Carlo Besta, Italy
  • 8. International School for Advanced Studies, Italy

Description

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, 61, 7640–7656 (DOI: 10.1021/acs.jmedchem.8b00610), © 2018 American Chemical Society, after peer review and technical editing by the publisher. To access the final edited and published work, see https://pubs.acs.org/articlesonrequest/AOR-yrCZV6e6VNr5AFhKcH79
This Manuscript version is made available under the CC-BY-NC-ND 4.0 license. https://creativecommons.org/licenses/by-nc-nd/4.0/

 

ABSTRACT

Several findings propose 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. In light of this and based on our interest in multi-target paradigms in AD, we report on the discovery of 2,4-thiazolidinedione-derivatives endowed with such profile. 28 and 30 displayed micromolar IC50 values towards 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, non-toxic, dual-acting compounds hitting tau cascade at two different hubs.

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