2. Neuronal Signaling
  3. Beta-secretase
  4. LY2811376

LY2811376 is the first orally available non-peptidic β-secretase (BACE1) inhibitor with IC50 of 239 nM-249 nM, that acts to decrease Aβ secretion with EC50 of 300 nM, and demonstrates to have 10-fold selectivity towards BACE1 over BACE2, and more than 50-fold inhibition over other aspartic proteases including cathepsin D, pepsin, or renin.

For research use only. We do not sell to patients.

LY2811376 Chemical Structure

LY2811376 Chemical Structure

CAS No. : 1194044-20-6

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10 mM * 1 mL in DMSO
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Customer Review

Based on 12 publication(s) in Google Scholar

LY2811376 Related Antibodies

Top Publications Citing Use of Products

    LY2811376 purchased from MedChemExpress. Usage Cited in: FEBS J. 2017 Apr;284(7):1096-1109.  [Abstract]

    SH-SY5Y cells are transfected with APPsw plasmid together with ciRS-7 plasmid or control plasmids for 48 h, then the transfected cells are treated with 100 μM BI LY2811376, or 20 μM TAPI or DMSO as vehicle control for an additional 12 h. Cell lysates are analyzed by 12% Tris/Tricine gel with C20 antibody to detect APP C-terminal fragments C99 and C83, 10% Tris/Tricine gel to detect full-length APP and NRG.

    View All Beta-secretase Isoform Specific Products:

    View All Isoforms
    BACE1 BACE2

    • Biological Activity

    • Protocol

    • Purity & Documentation

    • References

    • Customer Review

    Description

    LY2811376 is the first orally available non-peptidic β-secretase (BACE1) inhibitor with IC50 of 239 nM-249 nM, that acts to decrease Aβ secretion with EC50 of 300 nM, and demonstrates to have 10-fold selectivity towards BACE1 over BACE2, and more than 50-fold inhibition over other aspartic proteases including cathepsin D, pepsin, or renin.

    IC50 & Target

    BACE1

     

    Cellular Effect
    Cell Line Type Value Description References
    H4 IC50
    0.27 μM
    Compound: 1; LY2811376
    Inhibition of BACE1 in human H4 cells expressing APP751 Swedish mutant assessed as inhibition of amyloid beta 40 or amyloid beta 42 production incubated for 19 hrs by microplate reader analysis
    Inhibition of BACE1 in human H4 cells expressing APP751 Swedish mutant assessed as inhibition of amyloid beta 40 or amyloid beta 42 production incubated for 19 hrs by microplate reader analysis
    		[PMID: 26985314]
    HEK293 IC50
    0.239 μM
    Compound: 1; LY2811376
    Inhibition of human BACE1 (1 to 460 residues) expressed in HEK293 cells using mcaFRET peptide as substrate after 20 hrs by FRET assay
    Inhibition of human BACE1 (1 to 460 residues) expressed in HEK293 cells using mcaFRET peptide as substrate after 20 hrs by FRET assay
    		[PMID: 31786008]
    HEK293 IC50
    0.24 μM
    Compound: 1; LY2811376
    Inhibition of IgG1 Fc-fused human recombinant BACE1 (1 to 460 residues) expressed in HEK293 cells using methylcoumarin peptide harboring Swedish mutant as substrate incubated for 20 hrs by FRET assay
    Inhibition of IgG1 Fc-fused human recombinant BACE1 (1 to 460 residues) expressed in HEK293 cells using methylcoumarin peptide harboring Swedish mutant as substrate incubated for 20 hrs by FRET assay
    		[PMID: 26985314]
    HEK293 IC50
    0.3 μM
    Compound: 14
    Inhibition of BACE-1 in HEK293 cells expressing human APP751 cDNA harboring N670L671 mutation pretreated for 2 hrs followed by measuring after 2 hrs by sandwich ELISA
    Inhibition of BACE-1 in HEK293 cells expressing human APP751 cDNA harboring N670L671 mutation pretreated for 2 hrs followed by measuring after 2 hrs by sandwich ELISA
    		[PMID: 28749667]
    HEK293 EC50
    300 nM
    Compound: 38, LY-2811376
    Inhibition of BACE1 in HEK293 cells expressing APPswedish mutant assessed as inhibition of amyloid beta production by ELISA
    Inhibition of BACE1 in HEK293 cells expressing APPswedish mutant assessed as inhibition of amyloid beta production by ELISA
    		[PMID: 24704031]
    In Vitro

    In an APP-overexpressing human embryonic kidney cell line, LY2811376 treatment yields a concentration-dependent decrease in Aβ secretion with a half-maximal effective concentration (EC50) of appr 300 nM. LY2811376 treatment of primary neuronal cultures of PDAPP transgenic mouse produces a concentration-dependent decrease in Aβ secretion with an EC50 of appr 100 nM[1]. LY2811376 has good ADME properties (BACE1 IC50=240 nM, cellular potency IC50=300 nM) and selectivity (BACE2 and cathepsin D selectivity: appr 10- and 65-fold, respectively)[3]. LY2811376 reduces the Aβ40 levels in cortex and plasma without change of health and weight in a dose-dependent manner[4].

    MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

    LY2811376 Related Antibodies
    In Vivo

    LY2811376 (10, 30, and 100 mg/kg, p.o.) results in dose-dependent, significant reductions in Aβ as well as sAPPβ and C99, the proximal cleavage products of APP proteolysis by BACE1. LY2811376 produces dose-dependent decreases in all APP-related PD markers of BACE1 inhibition in PDAPP mice. Low (30 mg) and high (90 mg) doses of LY2811376 investigated in the CSF sampling study are based on PK and plasma Aβ1-40 PD observed in the SAD study[1]. LY2811376 (30 mg/kg, p.o.) can lead to a 60% decrease in the soluble Aβs in mouse cortex[2]. LY2811376 (100 mg/kg, p.o.) decreases the spine density and formation in mice. LY2811376 (100 mg/kg every 12 hours over 16 days) causes a reduction in the frequency of sEPSC and mEPSC, whereas the effects of LY2811376 on the amplitude of sEPSC fails to reach significance[4].

    MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
    Clinical Trial
    Molecular Weight

    320.36

    Formula

    C15H14F2N4S
    CAS No.
    Appearance

    Solid

    Color

    White to khaki

    SMILES

    FC1=C(C2=CN=CN=C2)C=C([C@]3(C)CCSC(N3)=N)C(F)=C1
    Shipping

    Room temperature in continental US; may vary elsewhere.
    Storage
    Powder -20°C 3 years
    4°C 2 years
    In solvent -80°C 2 years
    -20°C 1 year
    Solvent & Solubility
    In Vitro: 

    DMSO : ≥ 31 mg/mL (96.77 mM; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

    *"≥" means soluble, but saturation unknown.

    Preparing
    Stock Solutions
    Concentration Solvent Mass 1 mg 5 mg 10 mg
    1 mM 3.1215 mL 15.6074 mL 31.2149 mL
    5 mM 0.6243 mL 3.1215 mL 6.2430 mL
    View the Complete Stock Solution Preparation Table

    * Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
    Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.

    • Molarity Calculator

    • Dilution Calculator

    Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

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    Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

    This equation is commonly abbreviated as: C1V1 = C2V2

    Concentration (start)

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    In Vivo:

    Select the appropriate dissolution method based on your experimental animal and administration route.

    For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
    To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day.
    The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

    • Protocol 1

      Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% Saline

      Solubility: ≥ 2.5 mg/mL (7.80 mM); Clear solution

      This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).

      Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.

      Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
    • Protocol 2

      Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in Saline)

      Solubility: ≥ 2.5 mg/mL (7.80 mM); Clear solution

      This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).

      Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.

      Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
    In Vivo Dissolution Calculator
    Please enter the basic information of animal experiments:

    Dosage

    mg/kg

    Animal weight
    (per animal)

    g

    Dosing volume
    (per animal)

    μL

    Number of animals

    Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
    Please enter your animal formula composition:
    %
    DMSO +
    % 
    +
    %
    Tween-80 +
    %
    Saline
    Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
    The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
    Calculation results:
    Working solution concentration: mg/mL
    Method for preparing stock solution: mg drug dissolved in μL  DMSO (Stock solution concentration: mg/mL).
    The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
    Method for preparing in vivo working solution for animal experiments: Take μL DMSO stock solution, add μL . μL , mix evenly, next add μL Tween 80, mix evenly, then add μL Saline.
     If the continuous dosing period exceeds half a month, please choose this protocol carefully.
    Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
    Purity & Documentation

    Purity: 99.89%

    SDS (393 KB)

    COA (250 KB) LCMS (268 KB)

    Handling Instructions (2659 KB)
    References
    Animal Administration
    [1]

    Sprague Dawley [Crl:CD(SD)] rats (10 per sex per group), appr 7 weeks of age, are given 0 (vehicle only), 10, 30, or 100 mg/kg LY2811376 by daily oral gavage. Vehicle consists of 1% (w/v) hydroxyethylcellulose, 0.25% (v/v) polysorbate 80, and 0.05% (v/v) Dow Corning Antifoam 1510-US in reverse osmosis water. At necropsy after 3 months of treatment, tissues are immersion fixed in 10% neutral-buffered formalin (brain) or modified Davidson's solution (eyes) and then processed by routine methods to paraffin block and hematoxylin-eosin (H&E)-stained histologic slides. From selected animals given 100 mg/kg on a subsequent investigative study, eyes are fixed in modified Karnovsky's solution, processed routinely into epoxy resin, and then ultrathin sections stained with uranyl acetate and Sato's lead citrate are examined in a transmission electron microscope. In a separate study, BACE1 knock-out mice (B6.129-Bace1tm1Pcw/J) are given 0 or 100 mg/kg LY2811376 by daily oral gavage for 9 weeks, and then necropsied tissues are collected and examined by light microscopy as described above for the rat toxicology study.

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.
    References

    Complete Stock Solution Preparation Table

    * Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
    Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.

    Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
    DMSO 1 mM 3.1215 mL 15.6074 mL 31.2149 mL 78.0372 mL
    5 mM 0.6243 mL 3.1215 mL 6.2430 mL 15.6074 mL
    10 mM 0.3121 mL 1.5607 mL 3.1215 mL 7.8037 mL
    15 mM 0.2081 mL 1.0405 mL 2.0810 mL 5.2025 mL
    20 mM 0.1561 mL 0.7804 mL 1.5607 mL 3.9019 mL
    25 mM 0.1249 mL 0.6243 mL 1.2486 mL 3.1215 mL
    30 mM 0.1040 mL 0.5202 mL 1.0405 mL 2.6012 mL
    40 mM 0.0780 mL 0.3902 mL 0.7804 mL 1.9509 mL
    50 mM 0.0624 mL 0.3121 mL 0.6243 mL 1.5607 mL
    60 mM 0.0520 mL 0.2601 mL 0.5202 mL 1.3006 mL
    80 mM 0.0390 mL 0.1951 mL 0.3902 mL 0.9755 mL
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    LY2811376 Related Classifications

    Help & FAQs
    • Do most proteins show cross-species activity?

      Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

    Keywords:

    LY28113761194044-20-6LY 2811376LY-2811376Beta-secretaseBACEβ-SecretaseInhibitorinhibitorinhibit

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