ArticleJournal of Alzheimer's disease : JAD2016
AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics.
Article in Journal of Alzheimer's disease : JAD, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 129 citations in OpenAlex.
- Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials.JAMA neurology · 2020Trial
- Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of PF-06751979, a Potent and Selective Oral BACE1 Inhibitor: Results from Phase I Studies in Healthy Adults and Healthy Older Subjects.Journal of Alzheimer's disease : JAD · 2019Trial
- The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer's disease.EMBO molecular medicine · 2018Trial
- Clinical Bioavailability of the Novel BACE1 Inhibitor Lanabecestat (AZD3293): Assessment of Tablet Formulations Versus an Oral Solution and the Impact of Gastric pH on Pharmacokinetics.Clinical pharmacology in drug development · 2018Trial
- Small Molecule Therapeutics Targeting Amyloid-β in Alzheimer's Disease: Mechanisms, Clinical Progress, and Future Strategies.Experimental neurobiology · 2026Review
- Multitarget-directed ligands in Alzheimer's disease: identification of AChE and BACE1 inhibitors by in silico approaches.Journal of computer-aided molecular design · 2025Review
- Bacopa monnieri phytochemicals as promising BACE1 inhibitors for Alzheimer's disease therapy.Scientific reports · 2025Article
- Advance in peptide-based drug development: delivery platforms, therapeutics and vaccines.Signal transduction and targeted therapy · 2025Review
- Comprehensive investigation of multiple targets in the development of newer drugs for the Alzheimer's disease.Acta pharmaceutica Sinica. B · 2025Review
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- Silver nanoparticles alter the dimerization of AβRSC advances · 2024Article
- Article
- Bace1 Deletion in the Adult Reverses Epileptiform Activity and Sleep-wake Disturbances in AD Mice.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- BACE1 Inhibitors for Alzheimer's Disease: The Past, Present and Any Future?Molecules (Basel, Switzerland) · 2022Review
- Role of Natural Compounds and Target Enzymes in the Treatment of Alzheimer's Disease.Molecules (Basel, Switzerland) · 2022Review
- BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1.Science advances · 2022Article
- Small-molecule drugs development for Alzheimer's disease.Frontiers in aging neuroscience · 2022Review
- BACE1 controls synaptic function through modulating release of synaptic vesicles.Molecular psychiatry · 2021Article
- The case for low-level BACE1 inhibition for the prevention of Alzheimer disease.Nature reviews. Neurology · 2021Review
- An Overview of Several Inhibitors for Alzheimer's Disease: Characterization and Failure.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-β peptide (Aβ) concentrations, plays a key role in the pathogenesis of Alzheimer's disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-β protein precursor (AβPP) to Aβ peptides, with the soluble N terminal fragment of AβPP (sAβPPβ) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of Aβ. Here, we report the in vitro and in vivo pharmacological profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of Aβ. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.
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Registered trials
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.