Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer's disease

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.R.L. thanks Instituto de Salud Carlos III co-financed by the European Regional Development's funds (FEDER) for a research contract under Miguel Servet Program (CP11/00165) and financial support from the European Commission-REA, People (Marie Curie Actions) FP7 under REA grant agreement n° PCIG11-GA-2012-322156; Spanish Ministry of Health (Instituto de Salud Carlos III) (grant PI14/00372); Bayer AG, From Targets to Drugs (grant 2015-03-1282) and Fundación FIPSE (grant 12-00001344-15). Ministerio de Economía y Competitividad, MINECO (grant CTQ-2015-68380-R) to J.C.M and grant SAF2015-63935R to M.G.L.; GW thanks Cancer Research UK (grant C9344/A10268), the BBSRC (grant BB/L01923X/1), the Bloomsbury Consortium and UCL School of Pharmacy for financial support. G.T. thanks Universidad Complutense for a predoctoral fellowship. P.M. thanks MECD for FPU fellowship (FPU13/03737). I. G. thanks UAM for a FPI fellowship. We also gratefully acknowledge the continued support of Instituto-Fundación Teófilo Hernando, Madrid, Spain.Peer Reviewe