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    Neflamapimod (VX745, VRT031745; VD31745)
    Neflamapimod (VX745, VRT031745; VD31745)

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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 #: V0482
    CAS #: 209410-46-8Purity ≥98%

    Description:  Neflamapimod (formerly also known as VX-745, VRT-031745 and VD-31745) is a novel, highly potent and selective inhibitor of p38α MAPK with potential anti-inflammatory activity (e.g. anti-arthritis). It inhibits p38α MAPK with an IC50 of 10 nM, and shows 22-fold greater selectivity for p38α over p38β, and exhibits no inhibition to p38γ. VX-745 blocks TNFα production in LPS-stimulated HWB in vitro (IC50 = 177 nM). VX-745 displays excellent enzyme activity and selectivity, has a favorable pharmacokinetic profile, and demonstrates good in vivo activity in models of inflammation.

    References: Curr Opin Investig Drugs. 2001 Aug;2(8):1070-6; ACS Med Chem Lett, 2011, 2(10), 758-763.

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    Molecular Weight (MW)436.26
    FormulaC19H9Cl2F2N3OS
    CAS No.209410-46-8
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 15 mg/mL (34.4 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)30% PEG400+0.5% Tween80+5% propylene glycol: 30mg/mL
    Synonyms

    VD31745; VX 745; VX745; VRT 031745; VD 31745; VX-745; VRT-031745, VD-31745; VRT031745; 

    Chemical Name: 5-(2,6-Dichlorophenyl)-2-(2,4-difluorophenylsulfanyl)-6H-pyrimido[3,4-b]pyridazin-6-one

    InChi Key: VEPKQEUBKLEPRA-UHFFFAOYSA-N

    InChi Code: InChI=1S/C19H9Cl2F2N3OS/c20-11-2-1-3-12(21)17(11)18-14-5-7-16(25-26(14)9-24-19(18)27)28-15-6-4-10(22)8-13(15)23/h1-9H

    SMILES Code: O=C1C(C2=C(Cl)C=CC=C2Cl)=C3C=CC(SC4=CC=C(F)C=C4F)=NN3C=N1 


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    In Vitro

    In vitro activity: VX-745 selectively inhibits p38α and p38β MAPK with IC50 of 10 nM and 220 nM, respectively, but not p38γ MAPK and a large panel of other kinases, with IC50 larger than 20 µM. In a human peripheral blood mononuclear cell (PBMC) assay, VX-745 provides IC50 of 56 and 52 nM for IL-1β and TNFα, respectively. VX-745 blocks IL-6 and IL-8 production induced by IL-1 and TNFα, and COX-2 synthesis mediated by LPS and IL-1β. VX-745 (60 nM-20 µM) inhibits IL-6 and VEGF secretion in bone marrow stromal cells (BMSCs), without affecting their viability. VX-745 also inhibits TNF-α-induced IL-6 secretion in BMSCs. VX-745 inhibits both multiple myeloma (MM) cell proliferation and IL-6 secretion in BMSCs triggered by adherence of MM cells to BMSCs, suggesting that VX-745 can inhibit paracrine multiple myeloma (MM) cell growth in the BM milieu and overcome cell adhesion-related drug resistance.


    Kinase Assay: The IC50 for the inhibition of p38α and p38β homologs are obtained by a spectrophotometric coupled-enzyme assay. A fixed concentration of enzyme (15 nM of p38α or p38β) is incubated with VX-745 in DMSO for 10 min. at 30 °C in 0.1 M HEPES buffer, pH 7.5, containing 10% glycerol, 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200 µM NADH, 150 µg/mL pyruvate kinase, 50 µg/mL lactate dehydrogenase, and 200 µM EGF receptor peptide (KRELVEPLTPSGEAPNQALLR). The reaction is initiated with 100 µM and 70 µM ATP for p38α and p38β assays, respectively. The decrease of absorbance at 340 nm is monitored to follow the rate of the reaction. IC50 is evaluated from the rate data as a function of the inhibitor concentration.


    Cell Assay: BMSCs (5 × 104 cells/well) or MM cells (3 × 104 cells/well) are incubated in 96-well culture plates in the presence or absence of VX-745 for 48 hours at 37 °C. DNA synthesis is measured by [3H]-thymidine ([3H]TdR) uptake. Cells are pulsed with [3H]TdR (0.5 μCi/well [.0185 MBq]) during the last 8 hours of 48-hour cultures. Growth inhibition of both MM cells and BMSCs by VX-745 is also assessed by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) dye absorbance.

    In VivoVX-745 is effective against adjuvant-induced arthritis (AA) in the rat with ED50 of 5 mg/kg. Histological scores for VX-745 in AA rats are 93% inhibition of bone resorption and 56% inhibition of inflammation. In the classical cartilage-induced arthritis model, VX-745 exhibits a dose-responsive decrease in severity score. In a type II collagen-induced arthritis (CIA) mice model, VX-745 (2.5, 5, and 10 mg/kg) has 27%, 31%, and 44% improvement in the inflammatory scores, respectively, when compared to vehicle-treated mice. In addition, histological scores show a 32-39% protection of bone and cartilage erosion by VX-745
    Animal modelType II collagen-induced arthritis (CIA) mice model (DBA/1J)
    Formulation & DosageDissolved in 100% polyethylene glycol; 2.5, 5, and 10 mg/kg; p.o.
    References

    Curr Opin Investig Drugs. 2001 Aug;2(8):1070-6; ACS Med Chem Lett, 2011, 2(10), 758-763.


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

    VX-745

    Inhibitors of p38 MAP kinase.  2011 Jul 28;2(10):758-63.

    VX-745

    Structure of 3 bound to p38.  2011 Jul 28;2(10):758-63.

    VX-745

     2011 Jul 28;2(10):758-63.


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