LY2886721

Katalognr.S2156 Batch:S215603

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Tekniska data

Formel

C18H16F2N4O2S
Molekylvikt 390.41 CAS-nr. 1262036-50-9
Löslighet (25°C)* In vitro DMSO 35 mg/mL (89.64 mM)
Water Insoluble
Ethanol Insoluble
In Vivo (Tillsätt lösningsmedel till produkten individuellt och i ordning.)
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
* <1 mg/ml betyder svårlösligt eller olösligt.
* Vänligen notera att Selleck testar lösligheten för alla förbindelser internt, och den faktiska lösligheten kan skilja sig något från publicerade värden. Detta är normalt och beror på små variationer mellan olika partier.
* Rumstempererad frakt (Stabilitetstester visar att denna produkt kan fraktas utan några kylåtgärder.)

Beredning av stamlösningar

Biologisk aktivitet

Beskrivning LY2886721 är en BACE-hämmare som används för behandling av Alzheimers sjukdom. Fas 1/2.
Mål
BACE2
(Cell-free assay)		 BACE1
(Cell-free assay)
10.2 nM 20.3 nM
In vitro LY2886721 is an oral, small molecule of β-site amyloid protein cleaving enzyme (BACE) inhibitor with the potential to inhibit the synthesis of β-amyloid and thereby to slow the clinical progression of AD. This compound can also targetγ-secretase to nhibit the synthesis of β-amyloid. It inhibits recombinant hBACE1 with an IC50 of 20.3 nM. In cellular assays, this chemical inhibits Abeta with an IC50 of 18.7 nM and 10.7 nM, HEK293Swe and PDAPP neuronal culture, respectively. It has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Assessment of its activity against hBACE2 demonstrates an IC50 of 10.2 nM. Assessment of the compound's activity against cathepsin D, pepsin, renin, or other important aspartyl proteases shows essentially no inhibition (IC50 >100,000 nM), suggesting that activity against these common aspartyl proteases is unlikely to be significant.
In Vivo Oral administration of LY2886721 to PDAPP mice produces dose-dependent reductions in brain Abeta, C99 and sAPPbeta. Brain Abeta levels are decreased ∼20%-65% relative to vehicle-treated groups three hours after a 3-30 mg/kg dose of this compound. Brain C99 and sAPPb levels also are reduced in a dose-dependent manner consistent with BACE1 inhibition in vivo. The pharmacodynamic responses to this chemical persists out to 9 hours post dose in brains of PDAPP mice. Pharmacodynamic studies in beagle dog reveal robust and sustained reductions in plasma Abeta following 1 mg/kg dosing. Central effects of BACE1 inhibition in dog are manifested by a 50% reduction in CSF Abeta at 9 hours after a 0.5 mg/kg dose. The geometric mean terminal elimination t1/2 is determined to be 17.2 h (range 8.19-36.3 h). The geometric mean apparent oral clearance is 34.8 L/h (38% CV) and the apparent volume of distribution during the terminal phase was 863 L (56% CV) across dose levels. This compound is freely permeable across the blood-brain barrier.

Protokoll (från referens)

Cellanalys:

[4]
  • Cellinjer

    HEK293 cells

  • Koncentrationer

    --

  • Inkubationstid

    Overnight exposure

  • Metod

    A human embryonic kidney cell line (HEK293) stably expressing APP751cDNA containing a Swedish mutation (HEK293Swe) was exposed to increasing concentrations of LY2886721 and the amount of amyloid β1–40 (Aβ1-40) and Aβ1-42 measured in the media as an index of BACE1 inhibition. Compound cytotoxicity was assessed using a CellTiter96 Aqueous Non-Radioactive Cell Proliferation assay
Djurstudie:

[4]
  • Djurmodeller

    young PDAPP transgenic mice

  • Doseringar

    1.5 mg/kg

  • Administrering

    by oral gavage

Referenser

  • http://www.alz.org/ct/documents/adru_studies_2012_04_01.pdf
  • https://pubmed.ncbi.nlm.nih.gov/21368375/
  • http://www.alzheimersanddementia.com/article/S1552-5260(12)00367-6/abstract
  • https://pubmed.ncbi.nlm.nih.gov/25609634/

Kundvalidering av produkt

Data från [ , , Cell Discov, 2015, 1:15021. ]

Sellecks LY2886721 Har citerats av 23 Publikationer

Traumatic brain injury causes early aggregation of beta-amyloid peptides and NOTCH3 reduction in vascular smooth muscle cells of leptomeningeal arteries [ Acta Neuropathol, 2025, 149(1):10] PubMed: 39841284
Inhibition of Amyloid β Accumulation by Protease-Digested Whitebait (Shirasu) in a Murine Model of Alzheimer's Disease [ Foods, 2024, 13(18)2858] PubMed: 39335787
Familial Alzheimer's disease-associated PSEN1 mutations affect neurodevelopment through increased Notch signaling [ Stem Cell Reports, 2023, 18(7):1516-1533] PubMed: 37352850
Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine Loss [ Int J Mol Sci, 2022, 23(12)6637] PubMed: 35743082
Beta-Site Amyloid Precursor Protein-Cleaving Enzyme Inhibition Partly Restores Sevoflurane-Induced Deficits on Synaptic Plasticity and Spine Loss [ International Journal of Molecular Sciences, 2022, 6637] PubMed: 35743082
Aberrant role of pyruvate kinase M2 in the regulation of gamma-secretase and memory deficits in Alzheimer's disease [ Cell Rep, 2021, 37(10):110102] PubMed: 34879266
ST6GAL1 and α2-6 Sialylation Regulates IL-6 Expression and Secretion in Chronic Obstructive Pulmonary Disease [ Front Immunol, 2021, 12:693149] PubMed: 34290711
ST6GAL1 and α2-6 Sialylation Regulates IL-6 Expression and Secretion in Chronic Obstructive Pulmonary Disease [ Frontiers in Immunology, 2021, 693149] PubMed: 34290711
Pathological methamphetamine exposure triggers the accumulation of neuropathic protein amyloid-β by inhibiting UCHL1 [ Neurotoxicology, 2021, 86:19-25] PubMed: 34175320
Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain [ Mol Psychiatry, 2020, 10.1038/s41380-020-0806-5] PubMed: 32647257

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