ArticleJournal of medicinal chemistry2019
Conversion of Quinazoline Modulators from Inhibitors to Activators of β-Glucocerebrosidase.
Article in Journal of medicinal chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 26 citations in OpenAlex.
- A pH-Dependent Curcumin-Iminosugar Hybrid Promotes GCase Enhancement and Reactive Oxygen Species Reduction.ACS omega · 2026Article
- French national diagnosis and care protocol (Protocole National De Diagnostic et de Soins; PNDS): Gaucher disease.Orphanet journal of rare diseases · 2025Review
- An injectable hydrogel containingRSC advances · 2025Article
- Review
- GBA1 Variants and Parkinson's Disease: Paving the Way for Targeted Therapy.Journal of movement disorders · 2023Article
- Evaluation of Strategies for Measuring Lysosomal Glucocerebrosidase Activity.Movement disorders : official journal of the Movement Disorder Society · 2021Review
- iPSCs: A Preclinical Drug Research Tool for Neurological Disorders.International journal of molecular sciences · 2021Review
- Hydrogen peroxide-mediated synthesis of 2,4-substituted quinazolinesRSC advances · 2020Article
- Second-Generation Pharmacological Chaperones: Beyond Inhibitors.Molecules (Basel, Switzerland) · 2020Review
- Organoid and pluripotent stem cells in Parkinson's disease modeling: an expert view on their value to drug discovery.Expert opinion on drug discovery · 2020Review
- Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity.Human molecular genetics · 2020Article
- The Challenge of Disease-Modifying Therapies in Parkinson's Disease: Role of CSF Biomarkers.Biomolecules · 2020Review
- LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson's disease patients.Nature communications · 2019Article
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Gaucher's disease is a lysosomal disease caused by mutations in the β-glucocerebrosidase gene ( GBA1 and GCase) that have been also linked to increased risk of Parkinson's disease (PD) and Diffuse Lewy body dementia. Prior studies have suggested that mutant GCase protein undergoes misfolding and degradation, and therefore, stabilization of the mutant protein represents an important therapeutic strategy in synucleinopathies. In this work, we present a structure-activity relationship (SAR) study of quinazoline compounds that serve as inhibitors of GCase. Unexpectedly, we found that N-methylation of these inhibitors transformed them into GCase activators. A systematic SAR study further revealed that replacement of the key oxygen atom in the linker of the quinazoline derivative also contributed to the activity switch. PD patient-derived fibroblasts and dopaminergic midbrain neurons were treated with a selected compound (9q) that partially stabilized GCase and improved its activity. These results highlight a novel strategy for therapeutic development of noninhibitory GCase modulators in PD and related synucleinopathies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.