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    LY411575 (LY411575; LSN 411575)
    LY411575 (LY411575; LSN 411575)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0721
    CAS #: 209984-57-6Purity ≥98%

    Description: LY411575 (also named as LY-411575; LY 411575; LSN-411575; LSN411575) is a dibenzoazepine-based, cell permeable and selective Gamma/γ-secretase inhibitor with potential anti-AD ( Alzheimer's disease) activity. It inhibits γ-secretase with an IC50 of 0.078 nM/0.082 nM (membrane/cell-based), and also inhibits Notch cleavage with an IC50 of 0.39 nM in APP or NΔE expressing HEK293 cells. Acute or chronic treatment with LY 411575 is able to reduce the formation of Aβ/42, and block Notch activation, whichis a pathway regulating both differentiation and proliferation of cells in diverse adult tissues..

    References: J Biol Chem. 2004 Mar 26;279(13):12876-82; Oncogene. 2005 Sep 22;24(42):6333-44; J Pharmacol Exp Ther. 2006 Dec;319(3):1133-43. 

    Related CAS: 209984-58-7 (LY-411575 isomer 1)

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    Molecular Weight (MW)479.48
    FormulaC26H23F2N3O4
    CAS No.209984-57-6
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 95 mg/mL (198.1 mM)
    Water: <1 mg/mL
    Ethanol: 13 mg/mL (27.1 mM)
    Solubility (In vivo)30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL
    SynonymsLSN-411575; LSN-411575; LY 411575; LY-411575; LY411575; LSN 411575; LSN411575. 

    Chemical Name: N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide

    InChi Key: ULSSJYNJIZWPSB-CVRXJBIPSA-N

    InChi Code: InChI=1S/C26H23F2N3O4/c1-14(29-25(34)23(32)15-11-16(27)13-17(28)12-15)24(33)30-22-20-9-4-3-7-18(20)19-8-5-6-10-21(19)31(2)26(22)35/h3-14,22-23,32H,1-2H3,(H,29,34)(H,30,33)/t14-,22-,23-/m0/s1

    SMILES Code: C[[email protected]@H](C(N[[email protected]]1C2=CC=CC=C2C3=CC=CC=C3N(C)C1=O)=O)NC([[email protected]](C4=CC(F)=CC(F)=C4)O)=O


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    In Vitro

    In vitro activity: LY-411575 inhibits γ-secretase which can be assessed by the substrates like amyloid precursor protein (APP) and Notch S3 cleavage. LY-411575, which blocks Notch activation, results in apoptosis in primary and immortalized KS cells.


    Kinase Assay: Procedures for measuring γ-secretase activity in membranes prepared from HEK293 cells expressing APP have been described previously (Zhang L et al Biochemistry 40, 5049-5055). Intact HEK293 cells expressing either APP or NΔE are treated with various concentrations of LY- 411,575 for 4 hours at 37 °C. In the case of cells expressing NΔE, cells are lysed, the cell lysates are separated on a 4-12% NuPAGE gel, and the processed NICD fragment is detected via Western blot with a cleavage site-specific antibody. The inhibition of NICD production is quantified by spot densitometric analysis using FluorChem. In the case of cells expressing APP, the conditioned medium is collected, centrifuged at 10,000 × g for 5 minutes to remove cell debris, and stored at -20 °C prior to the determination of Aβ levels. Aβ40 and -42 produced in HEK293 membrane- and cell-based assays, as well as plasma Aβ40 and cortex Aβ40 from TgCRND8 mice, are analyzed without pretreatment using an electrochemiluminescence detection-based immunoassay. Plasma Aβ42 is measured by enzyme-linked immunosorbent assay. A commercially available enzyme-linked immunosorbent assay kit is used to measure cortex Aβ42 according to the manufacturer''s instructions.


    Cell Assay: DNA/PI staining is performed using standard methodologies. Briefly, 1 × 106 cells are permeabilized with 100% ethanol in the presence of 15% FBS. The cells are washed and then treated for 15 minutes at 37 °C with 10 mg/mL RNAse. PI (5 mg/mL) is added, and the cells incubated for 1 hour at 4 °C prior to analysis by flow cytometry with 10 000 cells analysed per gated determination. The results are confirmed using the Immunotech Annexin V staining kit following the manufacturers’ instructions. At least three independent experiments are performed showing similar results.

    In Vivo10 mg/kg oral dose of LY-411575 decreases brain and plasma Aβ40 and -42 dose-dependently. LY-411575 reduces cortical Aβ40 in young (preplaque) transgenic CRND8 mice (ED50 ≈ 0.6 mg/kg) and produces significant thymus atrophy and intestinal goblet cell hyperplasia at higher doses (>3 mg/kg). The therapeutic window is similar after oral and subcutaneous administration and in young and aged CRND8 mice. Both the thymus and intestinal side effects are reversible after a 2-week washout period. Three-week treatment with 1 mg/kg LY411575 reduces cortical Aβ40 by 69% without inducing intestinal effects, although a previously unreported change in coat color is observed.
    Animal modelTgCRND8 mice model
    Formulation & DosageFormulated as 10 mg/mL solutions in 50% polyethylene glycol, 30% propylene glycol, 10% ethanol and diluted in 0.4% methylcellulose for dosing.; 1-10 mg/kg; oral gavage
    References

    J Biol Chem. 2004 Mar 26;279(13):12876-82; Oncogene. 2005 Sep 22;24(42):6333-44; J Pharmacol Exp Ther. 2006 Dec;319(3):1133-43. 


    These protocols are for reference only. InvivoChem does not independently validate these methods.

     

    LY411575

    Time course of mechanism-based side effect onset caused by oral administration of 10 mg/kg LY411,575 in CRND8 mice. J Pharmacol Exp Ther. 2006 Dec;319(3):1133-43. 
     

    LY411575

    Representative ileum sections from CRND8 mice treated with vehicle (left column), LY411,575 (10 mg/kg p.o.; middle column), or LY-D (10 mg/kg p.o.; right column). J Pharmacol Exp Ther. 2006 Dec;319(3):1133-43. 
     

    LY411575

    Effects of LY411,575 (0.1–10 mg/kg) dosed orally (black bars) or subcutaneously (gray bars) and LY-D (10 mg/kg) dosed orally (cross-hatched bars) on efficacy and side effect measures assessed in CRND8 mice. J Pharmacol Exp Ther. 2006 Dec;319(3):1133-43. 
     

    LY411575

    Representative sections showing the dentate gyrus (DG), CA1, and CA3 regions of the hippocampus from a 12-week-old (A) and an 18-month-old (B) CRND8 mouse. J Pharmacol Exp Ther. 2006 Dec;319(3):1133-43. 
     

    LY411575

    J Pharmacol Exp Ther. 2006 Dec;319(3):1133-43.
     

    LY411575

    Effects of 6 (black bars) or 20 (diagonal striped bars) days of oral dosing with 1 mg/kg LY411,575 on thymus weight (A; n = 5/group) and percentage of villi area covered by PAS stain in the ileum (B; n = 6–8). J Pharmacol Exp Ther. 2006 Dec;319(3):1133-43. 


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