LY2886721

Catalog No.S2156 Batch:S215601

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Technical Data

Formula

C18H16F2N4O2S
Molecular Weight 390.41 CAS No. 1262036-50-9
Solubility (25°C)* In vitro DMSO 9 mg/mL (23.05 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description LY2886721 is a BACE inhibitor used for the treatment of Alzheimer's Disease. Phase 1/2.
Targets
BACE2 [4]
(Cell-free assay)		 BACE1 [4]
(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. [1] LY2886721 can also targetγ-secretase to nhibit the synthesis of β-amyloid[2]. LY2886721 inhibits recombinant hBACE1 with an IC50 of 20.3 nM. In cellular assays, LY2886721 inhibits Abeta with an IC50 of 18.7 nM and 10.7 nM, HEK293Swe and PDAPP neuronal culture, respectively[3]. LY2886721 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 LY2886721 activity against hBACE2 demonstrates an IC50 of 10.2 nM. Assessment of LY2886721 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[4].
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 LY2886721. Brain C99 and sAPPb levels also are reduced in a dose-dependent manner consistent with BACE1 inhibition in vivo. The pharmacodynamic responses to LY2886721 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 LY2886721 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 of LY2886721[3]. 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. LY2886721 is freely permeable across the blood-brain barrier[4].

Protocol (from reference)

Cell Assay:

[4]
  • Cell lines

    HEK293 cells

  • Concentrations

    --

  • Incubation Time

    Overnight exposure

  • Method

    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
Animal Study:

[4]
  • Animal Models

    young PDAPP transgenic mice

  • Dosages

    1.5 mg/kg

  • Administration

    by oral gavage

Customer Product Validation

Data from [Data independently produced by , , Cell Discov, 2015, 1:15021.]

Selleck's LY2886721 has been cited by 19 publications

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
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
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
Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signalling. [ Cell Death Dis, 2020, 11(2):98] PubMed: 32029735
Partial Reduction of Amyloid β Production by β-Secretase Inhibitors Does Not Decrease Synaptic Transmission [ Alzheimers Res Ther, 2020, 26;12(1):63] PubMed: 32456694
Multiple proteases are involved in mesothelin shedding by cancer cells [ Commun Biol, 2020, 3(1):728] PubMed: 33262421
Blood-Brain Barrier Dysfunction in a 3D In Vitro Model of Alzheimer's Disease. [ Adv Sci (Weinh), 2019, 6(20):1900962] PubMed: 31637161

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

NOT FOR HUMAN, VETERINARY DIAGNOSTIC OR THERAPEUTIC USE.