ArticleThe Journal of biological chemistry2012
Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 136 citations in OpenAlex.
- BACE-1 inhibitors as potential drug candidates for treatment of Alzheimer's disease: a systematic review.Molecular diversity · 2026Review
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- Identifying Potential BACE1 Inhibitors from the ChEMBL Database Using Machine Learning and Atomistic Simulation Approaches.ACS omega · 2026Article
- Targeting amyloid-β in Alzheimer's disease: A critical analysis of clinical trials and their implications for drug development.Iranian journal of basic medical sciences · 2026Review
- Nanoparticles with Ampholytic Surfaces for Binding and Disintegration of Amyloid Fibrils.ACS central science · 2025Article
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- Recent advances in potential enzymes and their therapeutic inhibitors for the treatment of Alzheimer's disease.Heliyon · 2024Review
- Impact of protein conformations on binding free energy calculations in the beta-secretase 1 system.Journal of computational chemistry · 2024Article
- ACEGEN: Reinforcement Learning of Generative Chemical Agents for Drug Discovery.Journal of chemical information and modeling · 2024Article
- Sulfone Electrophiles in Cross-Electrophile Coupling: Nickel-Catalyzed Difluoromethylation of Aryl Bromides.ACS catalysis · 2024Article
- Introduction of the difluoromethyl group at the meta- or para-position of pyridines through regioselectivity switch.Nature communications · 2024Article
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- Effect of Functional Inhibition of BACE1 on Sensitization to γ-Irradiation in Cancer Cells.Current issues in molecular biology · 2024Article
- Delta Machine Learning to Improve Scoring-Ranking-Screening Performances of Protein-Ligand Scoring Functions.Journal of chemical information and modeling · 2022Review
- Small-molecule drugs development for Alzheimer's disease.Frontiers in aging neuroscience · 2022Review
- Fragment-Based Drug Discovery by NMR. Where Are the Successes and Where can It Be Improved?Frontiers in molecular biosciences · 2022Article
- Targeting Amyloidogenic Processing of APP in Alzheimer's Disease.Frontiers in molecular neuroscience · 2020Review
- Bridging the Gap Between Fluid Biomarkers for Alzheimer's Disease, Model Systems, and Patients.Frontiers in aging neuroscience · 2020Review
- Multitarget Therapeutic Strategies for Alzheimer's Disease: Review on Emerging Target Combinations.BioMed research international · 2020Review
- Nitazoxanide, an anti-parasitic drug, efficiently ameliorates learning and memory impairments in AD model mice.Acta pharmacologica Sinica · 2019Article
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
β-Site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processing of the amyloid precursor protein (APP) and formation of amyloid β peptide (Aβ) species. Because cerebral deposition of Aβ species might be critical for the pathogenesis of Alzheimer disease, BACE1 has emerged as a key target for the treatment of this disease. Here, we report the discovery and comprehensive preclinical characterization of AZD3839, a potent and selective inhibitor of human BACE1. AZD3839 was identified using fragment-based screening and structure-based design. In a concentration-dependent manner, AZD3839 inhibited BACE1 activity in a biochemical fluorescence resonance energy transfer (FRET) assay, Aβ and sAPPβ release from modified and wild-type human SH-SY5Y cells and mouse N2A cells as well as from mouse and guinea pig primary cortical neurons. Selectivity against BACE2 and cathepsin D was 14 and >1000-fold, respectively. AZD3839 exhibited dose- and time-dependent lowering of plasma, brain, and cerebrospinal fluid Aβ levels in mouse, guinea pig, and non-human primate. Pharmacokinetic/pharmacodynamic analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects. These results suggest that AZD3839 effectively reduces the levels of Aβ in brain, CSF, and plasma in several preclinical species. It might, therefore, have disease-modifying potential in the treatment of Alzheimer disease and related dementias. Based on the overall pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man.
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