期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 17, 页码 7640-7656出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00610
关键词
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资金
- University of Bologna [RFO2015_2016]
- European Cooperation of Science and Technology (EUCOST) Action [CA15135]
- Ministerio de Economia y Competitividad [CTQ2015-66313-R]
- Italian Ministry of Health [GR-2013-02355724]
- MJFF
- ALZ
- Alzheimer's Research UK
- Weston Brain Institute (BAND2015)
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-3 beta 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-3 beta, together with the capacity of inhibiting AcPHF6 aggregation of 60% and 80% at 10 ktM, 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.
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