期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep45701
关键词
-
资金
- European Regional Development's funds (FEDER) [CP11/00165]
- European Commission-REA, People (Marie Curie Actions) FP7 under REA [PCIG11-GA-2012-322156]
- Spanish Ministry of Health (Instituto de Salud Carlos III) [PI14/00372]
- Bayer AG [2015-03-1282]
- Fundacion FIPSE [12-00001344-15]
- Ministerio de Economia y Competitividad, MINECO [CTQ-2015-68380-R, SAF2015-63935R]
- Cancer Research UK [C9344/A10268]
- BBSRC [BB/L01923X/1]
- Bloomsbury Consortium
- UCL School of Pharmacy
- Universidad Complutense
- MECD [FPU13/03737]
- UAM
- BBSRC [BB/L01923X/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/L01923X/1] Funding Source: researchfish
- Cancer Research UK [10268] Funding Source: researchfish
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 GSK3 beta 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 GSK3 beta inhibitors and Nrf2 inducers. These compounds are able to inhibit GSK3 beta 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据