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PF-06648671 | PF-06648671 : Modulator of PSEN1
RATINGS:
Cellular Use: (1 reviews)

In Model Organisms: (1 reviews)
Probe Summary
Selectivity
Potency
In Vivo
Control Compounds
Chemical Information
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Probe Summary

Targets Biochemical/Biophysical Potency Cellular Potency
PSEN1
    • IC50:9.8 nM
    Modulator
    up to 1 uM

    Selectivity

    In Vitro Selectivity Assessment
    Potency Assay Off-Target:
    Good selectivity was achieved over Notch (Notch intracellular domain, NICD) and hERG (>1,600-fold an ...

    Potency
    Cellular
    In Vitro

    PSEN1

    Mode of Action: Modulator

    Structure-Activity-Relationship data available? Yes

    DOI Reference: 10.1021/acs.jmedchem.4c00580

    In Vivo Validations

    Rat
    Dose: 10/40 mg/kg
    Route of delivery: Oral
    Plasma half life: 3.2 h determined from 1 mg/kg intravenous dose
    Systemic clearance: 3 mL/min/kg determined form 1 mg/kg intravenous dose
    Cmax: Plasma (ng/mL): 945,3220 at 10 mg/kg and 40 mg/kg respectively. Cerebellum (ng/mL): 1450,11300 at 10 mg/kg and 40 mg/kg respectively, CSF (ng/mL): 4.4, 21 at 10 mg/kg and 40 mg/kg respectively
    Tmax: 1h @10 mg/kg, 4h @40 mg/kg
    Area Under the Curve:: 6650 ng*h/mL @10 mg/kg, 27200 ng*h/mL @40 mg/kg
    Fb : 70% at 10mg/kg
    Bioavailability: 67% calculated using the exposure from 1 mg/kg intravenous dose and 5 mg/kg oral dose
    Volume of Distribution at Steady-State: 0.8 L/kg determined from 1 mg/kg intravenous dose
    Organ of interest (O): Brain

    DOI Reference: 10.1021/acs.jmedchem.4c00580

    Dog
    Dose: 5 mg/kg and 20 mg/kg
    Route of delivery: Oral
    Plasma half life: 7.7 h determined from 1mg/kg intravenous dose
    Systemic clearance: 1 mL/min/kg determined from 1 mg/kg intravenous dose
    Cmax: CSF (ng/mL): 3.42-6.33 @5 mg/kg, 11.3-21.8 @20 mg/kg
    Tmax: 2 h @5 mg/kg, 2-5 h @20 mg/kg
    Area Under the Curve:: CSF: 55-240 ng*h/mL @5 mg/kg, 257-893 ng*h/mL @20 mg/kg
    Bioavailability: 88% calculated using the exposure from 1 mg/kg intravenous dose and 5 mg/kg oral dose
    Volume of Distribution at Steady-State: 0.7 L/kg determined from 1 mg/kg intravenous dose
    Organ of interest (O): Brain

    DOI Reference: 10.1021/acs.jmedchem.4c00580

    Orthogonal Probes def

    E-2212

    Chemical Information

    Molecular Formula C25H23ClF4N4O3
    SMILEs Cc1cn(-c2ccc3n(c2=O)CCN([C@@H](C)[C@@H]2CC[C@H](c4cc(F)c(Cl)cc4C(F)(F)F)O2)C3=O)cn1
    InChI InChI=1S/C25H23ClF4N4O3/c1-13-11-32(12-31-13)19-3-4-20-24(36)33(7-8-34(20)23(19)35)14(2)21-5-6-22(37-21)15-9-18(27)17(26)10-16(15)25(28,29)30/h3-4,9-12,14,21-22H,5-8H2,1-2H3/t14-,21-,22+/m0/s1
    Molecular weight 538.14 Da
    AlogP 0.0
    HBond acceptors 7
    HBond donors --
    Atoms 60

    References

    Publications

    Cross References

    canSARChEMBLBindingDB

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    Expert Reviews

    by SERP
    (on 12 Dec 2024 )
    Cellular Use Rating
    In Model Organisms
    This is a well-characterised chemical probe. The data supporting potency, cellular efficacy and in vivo efficacy are well-described and use accepted models. The main limitation with regards to use of this...
    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