Gameiro, I;
Michalska, P;
Tenti, G;
Cores, A;
Buendia, I;
Rojo, AI;
Georgakopoulos, ND;
... Leon, R; + view all
(2017)
Discovery of the first dual GSK3 beta inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer's disease.
Scientific Reports
, 7
, Article 45701. 10.1038/srep45701.
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Abstract
The formation of neurofibrillary tangles (NFTs), oxidative stress and neuroinflammation have emerged as key targets for the treatment of Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder. These pathological hallmarks are closely related to the over-activity of the enzyme GSK3β and the downregulation of the defense pathway Nrf2-EpRE observed in AD patients. Herein, we report the synthesis and pharmacological evaluation of a new family of multitarget 2,4-dihydropyrano[2,3-c]pyrazoles as dual GSK3β inhibitors and Nrf2 inducers. These compounds are able to inhibit GSK3β and induce the Nrf2 phase II antioxidant and anti-inflammatory pathway at micromolar concentrations, showing interesting structure-activity relationships. The association of both activities has resulted in a remarkable anti-inflammatory ability with an interesting neuroprotective profile on in vitro models of neuronal death induced by oxidative stress and energy depletion and AD. Furthermore, none of the compounds exhibited in vitro neurotoxicity or hepatotoxicity and hence they had improved safety profiles compared to the known electrophilic Nrf2 inducers. In conclusion, the combination of both activities in this family of multitarget compounds confers them a notable interest for the development of lead compounds for the treatment of AD.
| Type: | Article |
|---|---|
| Title: | Discovery of the first dual GSK3 beta inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer's disease |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/srep45701 |
| Publisher version: | http://doi.org/10.1038/srep45701 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, TRANSCRIPTION FACTOR NRF2, CENTRAL-NERVOUS-SYSTEM, OXIDATIVE STRESS, NEURODEGENERATIVE DISEASES, ANTIOXIDANT RESPONSE, NEUROPROTECTIVE AGENTS, BIOLOGICAL EVALUATION, INDUCED NEUROTOXICITY, MEMORY IMPAIRMENT, NOX ENZYMES |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1550610 |
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