Trial reportThe Journal of neuroscience : the official journal of the Society for Neuroscience2011
Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor.
Trial report in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 165 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
165 citing papers in PubMed, 1 synthesis or guideline pooled it, 366 citations in OpenAlex.
- Notoginsenoside R1 for Organs Ischemia/Reperfusion Injury: A Preclinical Systematic Review.Frontiers in pharmacology · 2019Pooled it
- The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer's disease.EMBO molecular medicine · 2018Trial
- The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Trial
- An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter.Alzheimer's research & therapy · 2015Trial
- Recent advances towards BACE1 drug discovery and therapeutics design.RSC medicinal chemistry · 2026Review
- Review
- Key Chemotypes for the Rational Design of Dual AChE/BACE-1 Inhibitors.Current medicinal chemistry · 2026Review
- 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
- Article
- Translating Alzheimer's Disease Mechanisms into Therapeutic Opportunities.Biomolecules · 2025Review
- Exploration of Asparagus racemosus Willd for Alzheimer's Disease Through Integrated Metabolomics and Network Pharmacology Analyses Targeting BACE1 Protein.Neurochemical research · 2025Article
- "Advances in biomarker discovery and diagnostics for alzheimer's disease".Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Review
- Alzheimer's Is a Multiform Disease of Sustained Neuronal Integrated Stress Response Driven by the C99 Fragment Generated Independently of AβPP; Proteolytic Production of Aβ Is Suppressed in AD-Affected Neurons: Evolution of a Theory.International journal of molecular sciences · 2025Review
- Alzheimer's Disease Protein Targets: Comprehensive Review and Future Directions.Current pharmaceutical design · 2025Review
- Impact of protein conformations on binding free energy calculations in the beta-secretase 1 system.Journal of computational chemistry · 2024Article
- Enhanced phagocytosis associated with multinucleated microglia via Pyk2 inhibition in an acute β-amyloid infusion model.Journal of neuroinflammation · 2024Article
- Ectodomain shedding of PLA2R1 is mediated by the metalloproteases ADAM10 and ADAM17.The Journal of biological chemistry · 2024Article
- The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.The Journal of clinical investigation · 2024Article
- The amyloid precursor protein and its derived fragments concomitantly contribute to the alterations of mitochondrial transport machinery in Alzheimer's disease.Cell death & disease · 2024Article
- Review on anti-alzheimer drug development: approaches, challenges and perspectives.RSC advances · 2024Review
105 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
25 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimer's disease (AD) pathogenesis. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound Aβ-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aβ reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central Aβ reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.
Indexed as
Identifiers
What OpenQuestion holds
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.