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These pathological hallmarks are closely related to the over-activity of the enzyme GSK3\u03b2 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-<jats:italic>c<\/jats:italic>]pyrazoles as dual GSK3\u03b2 inhibitors and Nrf2 inducers. These compounds are able to inhibit GSK3\u03b2 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 <jats:italic>in vitro<\/jats:italic> models of neuronal death induced by oxidative stress and energy depletion and AD. Furthermore, none of the compounds exhibited <jats:italic>in vitro<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/srep45701","type":"journal-article","created":{"date-parts":[[2017,3,31]],"date-time":"2017-03-31T13:47:09Z","timestamp":1490968029000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":80,"title":["Discovery of the first dual GSK3\u03b2 inhibitor\/Nrf2 inducer. 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