title: Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer's disease.
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.
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina. Universidad Autónoma de Madrid, 28029 Madrid, Spain.|Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006 Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gameiro
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina. Universidad Autónoma de Madrid, 28029 Madrid, Spain.|Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006 Madrid, Spain.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Michalska
authors.affiliation: Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006 Madrid, Spain.
authors.forename: Giammarco
authors.initials: G
authors.lastname: Tenti
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Cores
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina. Universidad Autónoma de Madrid, 28029 Madrid, Spain.|Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006 Madrid, Spain.
authors.forename: Izaskun
authors.initials: I
authors.lastname: Buendia
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC y Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Rojo
authors.affiliation: UCL School of Pharmacy, University College London, 29/39 Brunswick Square, London WC1N 1AX UK.
authors.forename: Nikolaos D
authors.initials: ND
authors.lastname: Georgakopoulos
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina. Universidad Autónoma de Madrid, 28029 Madrid, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Hernández-Guijo
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Teresa Ramos
authors.affiliation: UCL School of Pharmacy, University College London, 29/39 Brunswick Square, London WC1N 1AX UK.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Wells
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina. Universidad Autónoma de Madrid, 28029 Madrid, Spain.|Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006 Madrid, Spain.
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC y Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuadrado
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: J Carlos
authors.initials: JC
authors.lastname: Menéndez
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina. Universidad Autónoma de Madrid, 28029 Madrid, Spain.|Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006 Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: León
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D055808:Drug Discovery; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control; D051267:NF-E2-Related Factor 2 / Q000819:agonists*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; C054369:MAPT protein, human; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D018696:Neuroprotective Agents; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta