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    Roflumilast
    Roflumilast

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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 #: V0777
    CAS #: 162401-32-3; Purity ≥98%

    Description: Roflumilast (BY-217; B 9302-107; BYK20869; Daxas; Daliresp) is anovel,  highly potent, selective, and long-acting  inhibitor of PDE4 with IC50 of 0.2-4.3 nM in a cell-free assay. It has anti-inflammatory effects and is under development as an orally administered drug for the treatment of inflammatory conditions of the lungs such as asthma, and chronic obstructive pulmonary disease (COPD). In vitro studies show that roflumilast inhibits the production of inflammatory mediators in a variety of human immune cells, suggesting a role for reducing COPD-related inflammation.

    References: Pulm Pharmacol Ther. 2010 Aug;23(4):235-56; J Pharmacol Exp Ther. 2001 Apr;297(1):267-79.

    Related CAS: 292135-78-5 (Roflumilast N-oxide); 1391052-76-8 (Roflumilast Impurity E)

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    Molecular Weight (MW)403.21
    FormulaC17H14Cl2F2N2O3
    CAS No.162401-32-3
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 81 mg/mL (200.9 mM)
    Water: <1 mg/mL
    Ethanol: 15 mg/mL (37.2 mM) 
    Solubility (In vivo)30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL
    SynonymsDaliresp; BY217; BY-217; B 9302-107; B-9302-107; APTA 2217, B9302-107, BY 217, BYK 20869; BYK-20869; BYK20869; Daxas; 


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    In Vitro

    In vitro activity: Roflumilast displays anti-inflammatory and immunomodulatory in vitro. Roflumilast inhibits LTB4 synthesis in human neutrophil with IC50 of 2 nM. Roflumilast inhibits fMLP-stimulated ROS formation as luminol-enhanced CL in human neutrophils or eosinophils with IC35 of 4 nM, and 7 nM, repectively. Roflumilast inhibits LPS-stimulated TNF-α synthesis in monocytes with IC40 of 21 nM. Roflumilast inhibits TNF-α synthesis in monocyte-derived dendritic cells with IC20 of 5 nM. Rolfumilast inhibits anti-CD3 and anti-CD28 antibody-stimulated proliferation of CD4+ T cells with IC30 of 7 nM. Rolfumilast inhibits anti-CD3 and anti-CD28 antibody-stimulated synthesis of IL-2, IL-4, IL-5, and IFN-v in CD4+ T cells with IC20 of 1 nM, IC30 of 7 nM, IC25 of 13 nM, and IC35 of 8 nM, respectively.


    Kinase Assay: PDE activity is determined with some modifications. The assay mixture contain 50 mM Tris (pH 7.4), 5 mM MgCl2, 0.5 μM cAMP or cGMP, and [3H]cAMP or [3H]cGMP (about 30,000 cpm/assay), the indicated concentration of the inhibitor and an aliquot of the enzyme solution at a final assay volume of 200 μL. Stock solutions of the compounds are diluted 1:100 (v/v) in the Tris buffer mentioned above; appropriate dilutions are prepared in 1% (v/v) DMSO/Tris buffer, which are diluted 1:2 (v/v) in the assays to obtain the desired final concentrations of the inhibitors at a DMSO concentration of 0.5% (v/v). DMSO itself affected none of the PDE activities. After preincubation for 5 min at 37°C, the reaction is started by the addition of substrate (cAMP or cGMP) and the assays are incubated for further 15 min at 37°C. Then 50 μL of 0.2 N HCl is added to stop the reaction and the assays are left on ice for about 10 min. Following incubation with 25 μg of 5′-nucleotidase (Crotalus atrox snake venom) for 10 min at 37°C, the assays are loaded on QAE Sephadex A-25 (1 mL of bed volume in Poly-Prep chromatography columns). The columns are eluted with 2 mL of 30 mM ammonium formate (pH 6.0) and the eluate is counted for radioactivity. Results are corrected for blank values (measured in the presence of denatured protein) that are below 5% of total radioactivity. The amount of cyclic nucleotides hydrolyzed did not exceed 30% of the original substrate concentration.


    Cell Assay: roflumilast does not affect PDE enzymes apart from PDE4, and is a subnanomolar inhibitor of most PDE4 splicing variants tested. It showed no PDE4 subtype selectivity apart from PDE4C (4C1, IC50=3 nM; 4C2, IC50=4.3 nM), which is inhibited with a slightly lower potency. Roflumilast is a potent and selective PDE4 inhibitor. Roflumilast is a monoselective PDE4 inhibitor since it does not affect other PDE isoenzymes, including PDE1, PDE2, PDE3, and PDE5 up to 10,000-fold higher concentrations. Roflumilast inhibits human neutrophil functions. Roflumilast inhibits TNFα synthesis in monocyte-derived dendritic cells. Rolfumilast inhibits proliferation and cytokine synthesis in CD4+ T cells. Proliferation is inhibited to a maximum of about 60% by Roflumilast with a potency (IC30) of 7 nM.

    In VivoRoflumilast is activity against pulmonary inflammatory response related to COPD in animal model. Roflumilast (5 mg/kg/day) induces reduction of neutrophils, macrophages, DC, B-cells, CD4+ T cells, CD8+ T cells in the lung of mice exposed to tobacco smoke for 7 month by 78%, 82%, 48%, 100%, 98%, and 88%, respectively. Roflumilast is an efficient inhibitor of lung fibrotic remodeling. Roflumilast dose-dependently diminishes total lung hydroxyproline after bleomycin, attaining about 47% inhibition at 5 mg/kg/day, paralleled by a reduction in lung αI(I) collagen transcripts and fibrotic lesions. Roflumilast reduces oxidative stress in vivo. Roflumilast (5 mg/kg/day) moderately reduces an increase in BAL fluid lipid hydroperoxides measured at day 14 after intratracheal bleomycin administration in mice.
    Animal modelCOPD Mice model
    Formulation & Dosage5 mg/kg
    ReferencesBMC Pulm Med. 2008 Aug 28;8:17. doi: 10.1186/1471-2466-8-17; Br J Pharmacol. 2009 Feb;156(3):534-44.


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

     


    Roflumilast


    Comparison of roflumilast and dexamethasone on lung αI(I)collagen mRNA and right ventricular hypertrophy associated with bleomycin in a therapeutic protocol in mice. Br J Pharmacol. 2009 Feb;156(3):534-44.
     


    Roflumilast


    Comparison of roflumilast (ROF) and methylprednisolone (MP) on lung αI(I)collagen mRNA and right ventricular hypertrophy associated with bleomycin in a therapeutic protocol in rats. Br J Pharmacol. 2009 Feb;156(3):534-44.


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