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NT-0796 | NT-0796 : Brain-Penetrant NLRP3 inhibitor of NLRP3
RATINGS:
Cellular Use: (2 reviews)

In Model Organisms: (2 reviews)
Probe Summary
Selectivity
Potency
In Vivo
Control Compounds
Chemical Information
References
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Probe Summary

Targets Biochemical/Biophysical Potency Cellular Potency
NLRP3
    • IC50:0.32 nM
    • IC50:2.1 nM
    Inhibitor
    10 nM

    Selectivity

    In Cell Selectivity Assessment
    Potency Assay Off-Target:
    NLRC4 inflammasome
    Selectivity Assessment Description:
    No effect at 3 nM
    In Vitro Selectivity Assessment
    Potency Assay Off-Target:
    cerep panel, 121 assays at 10 uM
    Selectivity Assessment Description:
    5HT2B antagonism (90% at 10 μM) only hit
    In Cell Selectivity Assessment
    Potency Assay Off-Target:
    PBMC IL-6 inhibition
    Selectivity Assessment Description:
    >2 μM IC50
    In Cell Selectivity Assessment
    Potency Assay Off-Target:
    PBMC TNFα inhibition
    Selectivity Assessment Description:
    >2 μM IC50
    In Cell Selectivity Assessment
    Potency Assay Off-Target:
    hERG patch clamp
    Selectivity Assessment Description:
    >30 μM IC50
    In Vitro Selectivity Assessment
    Potency Assay Off-Target:
    CYP IC50 (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 (midazolam))
    Selectivity Assessment Description:
    all >30 μM

    Potency
    Cellular
    In Vitro

    NLRP3

    Mode of Action: Inhibitor

    Structure-Activity-Relationship data available? Yes

    DOI Reference: 10.1021/acs.jmedchem.3c01398

    In Vivo Validations

    Mouse
    Dose: 3 mg/kg
    Route of delivery: Intravenous
    Cmax: 610 +/- 237 ng/mL
    Target engagement assay: brain concentration: 479 +/- 217 ng/g; blood/brain ratio 0.79 +/-0.2

    DOI Reference: 10.1021/acs.jmedchem.3c01398

    Chemical Information

    Molecular Formula C23H27N3O4
    SMILEs CC(C)OC(=O)[C@@H](Cc1ncccn1)OC(=O)Nc1c2c(cc3c1CCC3)CCC2
    InChI InChI=1S/C23H27N3O4/c1-14(2)29-22(27)19(13-20-24-10-5-11-25-20)30-23(28)26-21-17-8-3-6-15(17)12-16-7-4-9-18(16)21/h5,10-12,14,19H,3-4,6-9,13H2,1-2H3,(H,26,28)/t19-/m1/s1
    Molecular weight 409.20 Da
    AlogP 3.565400000000002
    HBond acceptors 7
    HBond donors 1
    Atoms 57

    Expert Reviews

    by SERP
    (on 19 Aug 2024 )
    Cellular Use Rating
    In Model Organisms
    Although the authors describe having conducted 'Cerep panel of 121 in vitro binding assays to assess its [NT-0796] selectivity across a broad range of biological receptors', no data has been provided for...
    by SERP
    (on 20 Aug 2024 )
    Cellular Use Rating
    In Model Organisms
    NT-0796 is an isopropyl ester pro-drug undergoing carboxylesterase-mediated cleavage to give its carboxylic acid product NDT-19795, which is a potent NLRP3 inhibitor (PBMC IC50 = 66 nM, WB IC50=4.7 μM)....
    Note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars. Read more about our evaluation criteria