ArticleScientific reports2017
Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer's disease.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed.
- Review
- Synthesis, Bioactivity and Molecular Modeling Studies on Benzimidazole Derivatives and Its Isosteres as Potent AChE/BChE and GSK3β Inhibitors for Alzheimer's Disease.Chemical biology & drug design · 2026Article
- The Synergistic Role of ApoE4 and GSK3β in Alzheimer's Disease: Pathological Mechanisms and Therapeutic Implications.Molecular neurobiology · 2025Review
- Fermented Soybean Pulp Alleviates Disease Progression of 5×FAD Model Mice.Molecular neurobiology · 2025Article
- Alcohol addiction and Alzheimer's disease: a molecular collision course.Translational psychiatry · 2025Review
- Novel Emerging Targets Identification in Reducing Risk of Alzheimer's Disease.Central nervous system agents in medicinal chemistry · 2025Review
- The Interplay of Protein Aggregation, Genetics, and Oxidative Stress in Alzheimer's Disease: Role for Natural Antioxidants and Immunotherapeutics.Antioxidants (Basel, Switzerland) · 2024Review
- Human dental pulp stem cells mitigate the neuropathology and cognitive decline via AKT-GSK3β-Nrf2 pathways in Alzheimer's disease.International journal of oral science · 2024Article
- Simvastatin-Mediated Nrf2 Activation Induces Fetal Hemoglobin and Antioxidant Enzyme Expression to Ameliorate the Phenotype of Sickle Cell Disease.Antioxidants (Basel, Switzerland) · 2024Article
- Recent Advancements in the Treatment of Alzheimer's Disease: A Multitarget-directed Ligand Approach.Current medicinal chemistry · 2024Review
- Neuroprotective Effects of N-methyl-(2S, 4R)-trans-4-hydroxy-L-proline (NMP) against Amyloid-β-Induced Alzheimer's Disease Mouse Model.Nutrients · 2023Article
- NRF2 Activation by Nitrogen Heterocycles: A Review.Molecules (Basel, Switzerland) · 2023Review
- GSK3 Is a Central Player in Retinal Degenerative Diseases but a Challenging Therapeutic Target.Cells · 2022Review
- Resveratrol-Based MTDLs to Stimulate Defensive and Regenerative Pathways and Block Early Events in Neurodegenerative Cascades.Journal of medicinal chemistry · 2022Article
- Novel Series of Dual NRF2 Inducers and Selective MAO-B Inhibitors for the Treatment of Parkinson's Disease.Antioxidants (Basel, Switzerland) · 2022Article
- Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation.Antioxidants (Basel, Switzerland) · 2021Article
- Article
- Oxyphylla A ameliorates cognitive deficits and alleviates neuropathology via the Akt-GSK3β and Nrf2-Keap1-HO-1 pathways inJournal of advanced research · 2021Article
- Glycogen Synthase Kinase-3: A Focal Point for Advancing Pathogenic Inflammation in Depression.Cells · 2021Review
- GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways.International journal of molecular sciences · 2021Review
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Authors and funding
14 authors.
Funding
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.
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