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    BIRB 796 (Doramapimod)
    BIRB 796 (Doramapimod)

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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 #: V0477
    CAS #: 285983-48-4Purity ≥98%

    Description: BIRB 796 (also known as doramapimod) is a novel, orally bioactive, and highly potent pan-p38 MAPK inhibitor with potential anti-inflammatory activity. It inhibits p38α/β/γ/δ with IC50s of 38 nM, 65 nM, 200 nM and 520 nM in cell-free assays, and binds to p38α with a Kd of 0.1 nM in THP-1 cells. It shows 330-fold higher selectivity for p38α/β/γ/δ over JNK2, and has weak inhibition for c-RAF, Fyn and Lck. BIRB 796 (30 mg/kg) inhibits 84% of TNF-α in LPS-stimulated mice and demonstrates efficacy in a mouse model of established collagen-induced arthritis.  BIRB-796 is a member of the N-pyrazole-N'-naphthly urea class of p38MAPK inhibitors which binds to the kinase with both slow association and dissociation rates. BIRB -796 has entered clinical trials for the treatment of autoimmune diseases. 

    References: Nat Struct Biol. 2002 Apr;9(4):268-72; J Med Chem. 2002 Jul 4;45(14):2994-3008.

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    Molecular Weight (MW)527.66
    FormulaC31H37N5O3
    CAS No.285983-48-4
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 106 mg/mL (200.9 mM)
    Water: <1 mg/mL
    Ethanol: 106 mg/mL (200.9 mM)
    Solubility (In vivo)30% PEG400+0.5% Tween80+5% Propylene glycol: 30 mg/mL
    Synonyms

    BIRB796; BIRB-796; Doramapimod; BIRB 796

    Chemical Name: 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-(2-morpholinoethoxy)naphthalen-1-yl)urea.

    InChi Key: MVCOAUNKQVWQHZ-UHFFFAOYSA-N

    InChi Code: InChI=1S/C31H37N5O3/c1-22-9-11-23(12-10-22)36-29(21-28(34-36)31(2,3)4)33-30(37)32-26-13-14-27(25-8-6-5-7-24(25)26)39-20-17-35-15-18-38-19-16-35/h5-14,21H,15-20H2,1-4H3,(H2,32,33,37)

    SMILES Code: O=C(NC1=C2C=CC=CC2=C(OCCN3CCOCC3)C=C1)NC4=CC(C(C)(C)C)=NN4C5=CC=C(C)C=C5 


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    In Vitro

    In vitro activity: BIRB 796 shows no significant inhibition to ERK-1, SYK, IKK2β, ZAP-70, EGF receptor kinase, HER2, protein kinase A (PKA), PKC, PKC-α, PKC-β (I and II) and PKC-γ. BIRB 796 greatly improves binding affinity by forming a hydrogen bond between the morpholine oxygen and the ATP-binding domain of p38α. BIRB 796 represents one of the most potent and slowest dissociating inhibitors against human p38 MAP kinase now known. BIRB 796 potently inhibits c-Raf-1 and Jnk2α2 with IC50 of 1.4 and 0.1 nM, respectively. BIRB796 also inhibits the activity and the activation of SAPK3/p38γ at a higher concentration than it does in p38α. BIRB796 blocks the stress-induced phosphorylation of the scaffold protein SAP97, which is a physiological substrate of SAPK3/p38γ. BIRB796 blocks JNK1/2 activation and activity in HEK293 cells, while not inhibits the activation and activity of ERK1/ERK2 in Hela cells. Moreover, the binding of BIRB796 to the p38 MAPKs or JNK1/2 is impairing their phosphorylation by the upstream kinase MKK6 or MKK4 rather than enhancing their dephosphorylation. BIRB 796 blocks baseline and bortezomib-triggered upregulation of p38 MAPK and Hsp27 phosphorylation, thereby enhancing cytotoxicity and caspase activation. BIRB 796 downregulates IL-6 and VEGF secretion in BMSCs triggered by TNF-α and TGF-β1. BIRB-796 has a pyrazole scaffold that places a lipophilic t-butyl group into the lower selectivity site and a tolyl ring into the upper selectivity site. BIRB-796 also inhibits B-Raf and Abl with IC50 of 83 nM and 14.6 μM, respectively.


    Kinase Assay: BIRB 796 (Doramapimod) is a highly selective p38α inhibitor of MAPK with Kd of 0.1 nM, 330-fold greater selectivity versus JNK2, weak inhibition for c-RAF, Fyn and Lck, insignificant inhibition of ERK-1, SYK, IKK2, ZAP-70, EGFR, HER2, PKA, PKC, PKCα/β/γ.


    Cell Assay: BIRB 796 inhibited baseline and Dex-induced phosphorylation of both p38 MAPK and Hsp27 in MM.1S cells. Although MM.1S cell proliferation was strongly inhibited by Dex alone at 24–72 h, BIRB 796 significantly enhanced its growth inhibition. Cell cycle profiling suggests that BIRB 796 augmented Dex-mediated growth inhibition by enhancing apoptosis (Sub-G1 portion: control = 6.1%, BIRB 796 alone = 8.0%, Dex alone = 34.7%, BIRB 796 plus Dex = 45.7%).

    In VivoBIRB 796 (30 mg/kg) inhibits 84% of TNF-α in LPS-stimulated mice and demonstrates efficacy in a mouse model of established collagen-induced arthritis. BIRB 796 has good pharmacokinetic performance even after oral administration in mice.
    Animal modelCollagen-induced arthritis in female Balb/c mice
    Formulation & DosageDissolved in 70% PEG400 (intravenous) or 100% PEG400 (oral); 1 mg/kg (intravenous) or 10 mg/kg (oral);   i.v. injection or p.o.
    References

    Nat Struct Biol. 2002 Apr;9(4):268-72; J Med Chem. 2002 Jul 4;45(14):2994-3008.


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

    BIRB 796 (Doramapimod)

    BIRB 796 (Doramapimod)


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