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    Avagacestat (BMS-708163)
    Avagacestat (BMS-708163)

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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 #: V0718
    CAS #: 1146699-66-2Purity ≥98%

    Description: Avagacestat (formerly known as BMS708163) is a potent, selective, orally bioactive γ -secretase inhibitor of Aβ40 and Aβ42 with potential anti-AD (Alzheimer's disease) activity. It inhibits Aβ40 and Aβ42 with IC50 of 0.3 nM and 0.27 nM, it demonstrated a 193-fold selectivity against Notch. Avagacestat is designed for selective inhibition of Aβ synthesis currently in development for the treatment of mild to moderate and predementia AD. Avagacestat produced up to 190-fold greater selectivity for Aβ synthesis than Notch processing in preclinical studies and may therefore produce less toxic adverse events than other less selective compounds.

    References: Med Chem Lett, 2010, 1 (3), 120–124.

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    Molecular Weight (MW)520.88
    FormulaC20H17ClF4N4O4S
    CAS No.1146699-66-2
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 104 mg/mL (199.7 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    SMILESO=C(N)[[email protected]](N(CC1=CC=C(C2=NOC=N2)C=C1F)S(=O)(C3=CC=C(Cl)C=C3)=O)CCC(F)(F)F
    SynonymsBMS-708163; BMS708163; Avagacestat; BMS 708163. 

    Chemical Name: (R)-2-(4-chloro-N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide

    InChi Key: MKQKPLQMNCXTJE-VEZQGTPESA-L

    InChi Code: InChI=1S/C22H25N6O8P.2Na/c1-2-23-22(29)27-19-16-20(25-11-24-19)28(12-26-16)21-18-17(14(34-21)10-33-37(30,31)32)35-15(36-18)9-8-13-6-4-3-5-7-13;;/h3-9,11-12,14-15,17-18,21H,2,10H2,1H3,(H2,30,31,32)(H2,23,24,25,27,29);;/q;2*+1/p-2/b9-8+;;/t14-,15+,17-,18-,21-;;/m1../s1


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    In Vitro

    In vitro activity: BMS-708163 exhibits weaker selectivity for inhibition of Notch processing with 193-fold IC50 value.


    Kinase Assay: Avagacestat (BMS-708163) is a potent inhibitor of γ-secretase, with IC50s of 0.27 nM and 0.30 nM for Aβ42 and Aβ40 inhibition; Avagacestat (BMS-708163) also inhibits NICD (Notch IntraCellular Domain) with IC50 of 0.84 nM and shows weak inhibition of CYP2C19, with IC50 of 20 μM.


    Cell Assay: The cell viability is assessed using a tetrazolium salt (WST-8)-based colorimetric assay from the Cell Counting Kit 8 (CCK-8). The cells are seeded into 96-well plates at an initial density of 5×103 cells/well and cultured for 24 h, after which the cells are cultured with DMSO, increased concentrations of gefitinib or Avagacestat (BMS-708163) , BIBW2992, or the combination of Avagacestat (BMS-708163) and BIBW2992 for an additional 48 h. The A450 is measured in a microplate reader after 10 µL of CCK-8 solution is added and incubated for 1 h. The percentage of growth is shown relative to untreated controls.

    In VivoOral administration of BMS-708163 significantly reduces Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs. BMS-708163 has no dose-limiting effects in dogs (3 mg/kg during 6 months), with a high brain to plasma ratio (2.4).
    Animal modelFemale Harlan Sprague-Dawley rats or ATM-405-142K9 with 7- 10 month old Naive, grade II beagles
    Formulation & DosageDissolved in 99% PEG-400, 1% Tween-80 (rats) or 94% labrafil-1944, 5% ethanol, 1% tween-80 (dogs);  10 mg/kg (rats) or 2.5 mg/kg (dogs); Oral gavage
    ReferencesMed Chem Lett, 2010, 1 (3), 120–124.


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

     
    Avagacestat (BMS-708163)
    ACS Med. Chem. Lett., 2010, 1 (3), pp 120–124.



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