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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