DS-1971a | Inhibitor of SCN9A
RATINGS:
Cellular Use: (3 reviews)

In Model Organisms: (3 reviews)
Control Compounds

Probe Summary

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Targets Biochemical/Biophysical Potency Cellular Potency
SCN9A
    • IC50:24.5 nM Human; 26.5 nM Mouse
    Inhibitor
    100 - 1000 nM

    Selectivity

    In Cell Selectivity Assessment
    Selectivity Assessment Description:
    <strong>Within Target Family: </strong>Weak inhibitory activity was observed against hNaV1.2 and ...

    Potency
    Cellular
    In Vitro

    SCN9A

    Mode of Action: Inhibitor

    Structure-Activity-Relationship data available? No

    DOI Reference: 10.1021/acs.jmedchem.0c00259

    In Vivo Validations

    Mouse
    Dose: 1 mg/Kg
    Route of delivery: Intravenous, Oral
    Plasma half life: 2.02 h
    Systemic clearance: 78.7 mL/min/kg
    Cmax: 105 nM
    Tmax: 0.0833 h
    Area Under the Curve:: 68.9 h*nM
    Bioavailability: 15%
    Volume of Distribution at Steady-State: 1.37 L/Kg

    DOI Reference: 10.1021/acs.jmedchem.0c00259

    Dose: 3 mg/Kg
    Route of delivery: Intravenous, Oral
    Plasma half life: 1.54 h
    Systemic clearance: 45.3 mL/min/Kg
    Cmax: 464 nM
    Tmax: 0.250 h
    Area Under the Curve:: 277 h*nM
    Bioavailability: 11%
    Volume of Distribution at Steady-State: 0.565 L/Kg

    DOI Reference: 10.1021/acs.jmedchem.0c00259

    Rat
    Dose: 1 mg/Kg
    Route of delivery: Intravenous, Oral
    Plasma half life: 0.77 h
    Systemic clearance: 45 mL/min/kg
    Cmax: 103 ± 40.8 nM
    Tmax: 0.50 ± 0.00 h
    Area Under the Curve:: 103 h*nM
    Bioavailability: 16 ± 6.5%
    Volume of Distribution at Steady-State: 1.2 L/Kg

    DOI Reference: 10.1021/acs.jmedchem.0c00259

    Dog
    Dose: 1 mg/Kg
    Route of delivery: Intravenous, Oral
    Plasma half life: 4.0 h
    Systemic clearance: 8.7 mL/min/kg
    Cmax: 1708 nM
    Tmax: 0.50 h
    Area Under the Curve:: 3230 h*nM
    Bioavailability: 77%
    Volume of Distribution at Steady-State: 0.57 L/Kg

    DOI Reference: 10.1021/acs.jmedchem.0c00259

    Monkey (Cynomolgus)
    Dose: 1 mg/Kg
    Route of delivery: Intravenous, Oral
    Plasma half life: 3.69 ± 0.18 h
    Systemic clearance: 6.55 ± 1.62 mL/min/Kg
    Cmax: 1570 ± 648 nM
    Tmax: 0.83 ± 0.29 h
    Area Under the Curve:: 2060 ± 923 h*nM
    Bioavailability: 35 ± 10%
    Volume of Distribution at Steady-State: 0.150 ± 0.009 L/Kg

    DOI Reference: 10.1021/acs.jmedchem.0c00259

    Orthogonal Probes def

    PF-05089771

    Chemical Information

    Molecular Formula C20H21ClFN5O3S
    SMILEs Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
    InChI InChI=1S/C20H21ClFN5O3S/c1-27-16(6-9-25-27)13-4-2-3-5-17(13)30-18-11-15(22)19(10-14(18)21)31(28,29)26-20-7-8-23-12-24-20/h6-13,17H,2-5H2,1H3,(H,23,24,26)/t13-,17+/m1/s1
    Molecular weight 465.10 Da
    AlogP 3.9086000000000025
    HBond acceptors 8
    HBond donors 1
    Atoms 52

    References

    Cross References

    ChEMBL BindingDB PubChem canSAR

    Vendors

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    Expert Reviews


    (on 28 Jul 2021)
    Cellular Use Rating
    In Model Organisms
    Good to see some PK/PD relating exposure to efficacy. It has been hypothesised efficacy in mice is driven by greater target residence, leading to free EC50=1.1nM compared to the in vitro mNa1.7 IC50=59.4nM....
    (on 13 Aug 2021)
    Cellular Use Rating
    In Model Organisms
    (The reviewer did not leave any public comments)
    (on 2 Sept 2021)
    Cellular Use Rating
    In Model Organisms
    This compound seems to be very well profiled. Selectivity within target family and also outside. ADME and PK/PD profiled in 4 species. Has been in phase 1 (chronic pain) and phase 2 initiated on diabetic...
    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