JNJ-54175446

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Synonyms
Status
Molecule Category UNKNOWN
UNII 32524GLF40

Structure

InChI Key CWFVVQFVGMFTBD-SECBINFHSA-N
Smiles C[C@@H]1c2nnn(-c3ncc(F)cn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
InChI
InChI=1S/C18H13ClF4N6O/c1-9-15-13(29(27-26-15)17-24-7-10(20)8-25-17)5-6-28(9)16(30)11-3-2-4-12(14(11)19)18(21,22)23/h2-4,7-9H,5-6H2,1H3/t9-/m1/s1

Physicochemical Descriptors

Property Name Value
Molecular Formula C18H13ClF4N6O
Molecular Weight 440.79
AlogP 3.63
Hydrogen Bond Acceptor 6.0
Hydrogen Bond Donor 0.0
Number of Rotational Bond 2.0
Polar Surface Area 76.8
Molecular species NEUTRAL
Aromatic Rings 3.0
Heavy Atoms 30.0

Bioactivity

Mechanism of Action Action Reference
P2X purinoceptor 7 antagonist ANTAGONIST ClinicalTrials PubMed PubMed PubMed
Protein: P2X purinoceptor 7
Description: P2X purinoceptor 7
Organism : Homo sapiens
Q99572 ENSG00000089041
Targets EC50(nM) IC50(nM) Kd(nM) Ki(nM) Inhibition(%)
Enzyme Cytochrome P450 Cytochrome P450 family 2 Cytochrome P450 family 2C Cytochrome P450 2C8
- 9600 - - -
Ion channel Ligand-gated ion channel P2X receptor
- 4-20 - 5 -
Assay Description Organism Bioactivity Reference
Radioligand Binding Assay: human or rat P2X7-1321 N1 cells were collected and frozen @−80° C. On the day of the experiment, cell membrane preparations were made according to standard published methods. The total assay volume was 100 μl: 10 μl compound (10×)+(b) 40 μl tracer (2.5×)+50 μl membrane (2×). The tracer used for the assay was tritiated A-804598. The compound can be prepared as described in the literature. (Donnelly-Roberts, D. Neuropharmacology 2009, 56 (1), 223-229.) Compounds, tracer and membranes were incubated for 1 hour @ 4° C. The assay was terminated by filtration (GF/B filters pre-soaked with 0.3% PEI) and washed with washing buffer (Tris-HCl 50 mM). None 9.4 nM
Radioligand Binding Assay: human or rat P2X7-1321 N1 cells were collected and frozen @−80° C. On the day of the experiment, cell membrane preparations were made according to standard published methods. The total assay volume was 100 μl: 10 μl compound (10×)+(b) 40 μl tracer (2.5×)+50 μl membrane (2×). The tracer used for the assay was tritiated A-804598. The compound can be prepared as described in the literature. (Donnelly-Roberts, D. Neuropharmacology 2009, 56 (1), 223-229.) Compounds, tracer and membranes were incubated for 1 hour @ 4° C. The assay was terminated by filtration (GF/B filters pre-soaked with 0.3% PEI) and washed with washing buffer (Tris-HCl 50 mM). None 5.5 nM
FLIPR Assay: 1321 N1 cells expressing the recombinant human, rat or mouse P2X7 channel was cultured in HyQ DME/(HyClone/Dulbecco's Modified Eagle Medium) high glucose supplemented with 10% Fetal Bovine Serum (FBS) and appropriate selection marker. Cells were seeded at a density of 25000 cells/well (96-well clear bottom black walled plates) in 100 ul volume/well. On the day of the experiment, cell plates were washed with assay buffer, containing (in mM): 130 NaCl, 2 KCl, 1 CaCl2, 1 MgCl2, 10 HEPES, 5 glucose; pH 7.40 and 300 mOs. After the wash, cells were loaded with the Calcium-4 dye (Molecular Device) and incubated in the dark for 60 minutes. Test compounds were prepared at 250ÿ the test concentration in neat DMSO. Intermediate 96-well compound plates were prepared by transferring 1.2 uL of the compound into 300 uL of assay buffer. A further 3x dilution occurred when transferring 50 uL/well of the compound plate to 100 uL/well in the cell plate. Cells were incubate  with test compounds and dye for 30 minutes. Calcium dye fluorescence was monitored in FLIPR as the cells were challenged by adding 50 uL/well of BzATP (final concentration is 250 uM BzATP (human and rat) or 600 (mouse)). The fluorescence change was measured 180 seconds after adding the agonist. None 3.0 nM
FLIPR Assay: 1321 N1 cells expressing the recombinant human, rat or mouse P2X7 channel was cultured in HyQ DME/(HyClone/Dulbecco's Modified Eagle Medium) high glucose supplemented with 10% Fetal Bovine Serum (FBS) and appropriate selection marker. Cells were seeded at a density of 25000 cells/well (96-well clear bottom black walled plates) in 100 ul volume/well. On the day of the experiment, cell plates were washed with assay buffer, containing (in mM): 130 NaCl, 2 KCl, 1 CaCl2, 1 MgCl2, 10 HEPES, 5 glucose; pH 7.40 and 300 mOs. After the wash, cells were loaded with the Calcium-4 dye (Molecular Device) and incubated in the dark for 60 minutes. Test compounds were prepared at 250ÿ the test concentration in neat DMSO. Intermediate 96-well compound plates were prepared by transferring 1.2 uL of the compound into 300 uL of assay buffer. A further 3x dilution occurred when transferring 50 uL/well of the compound plate to 100 uL/well in the cell plate. Cells were incubate  with test compounds and dye for 30 minutes. Calcium dye fluorescence was monitored in FLIPR as the cells were challenged by adding 50 uL/well of BzATP (final concentration is 250 uM BzATP (human and rat) or 600 (mouse)). The fluorescence change was measured 180 seconds after adding the agonist. None 18.8 nM
Antagonist activity at P2X7 in rat brain cortex Rattus norvegicus 10.0 nM
Antagonist activity at P2X7 in human PBMC assessed as inhibition of BzATP-induced IL-1beta release preincubated for 30 mins followed by BzATP addition measured after 1.5 hrs by ELISA Homo sapiens 19.95 nM
Antagonist activity at P2X7 in dog whole blood assessed as inhibition of BzATP-induced IL-1beta release preincubated for 30 mins followed by BzATP addition measured after 1.5 hrs by ELISA Canis lupus familiaris 158.49 nM
Antagonist activity at P2X7 in mouse whole blood assessed as inhibition of BzATP-induced IL-1beta release preincubated for 30 mins followed by BzATP addition measured after 1.5 hrs by ELISA Mus musculus 31.62 nM
Antagonist activity at P2X7 in human whole blood assessed as inhibition of BzATP-induced IL-1beta release preincubated for 30 mins followed by BzATP addition measured after 1.5 hrs by ELISA Homo sapiens 7.943 nM
Displacement of [3H]-A-804598 from recombinant human P2X7 expressed in human 1321N1 cells after 1 hr Homo sapiens 5.012 nM
Displacement of [3H]-A-804598 from recombinant rat P2X7 expressed in human 1321N1 cells after 1 hr Rattus norvegicus 5.012 nM
Antagonist activity at macaque P2X7 assessed as inhibition of BzATP-induced calcium flux preincubated for 30 mins followed by BzATP addition measured over 180 secs by FLIPR assay Macaca mulatta 7.943 nM
Antagonist activity at dog P2X7 assessed as inhibition of BzATP-induced calcium flux preincubated for 30 mins followed by BzATP addition measured over 180 secs by FLIPR assay Canis lupus familiaris 12.59 nM
Antagonist activity at mouse P2X7 assessed as inhibition of BzATP-induced calcium flux preincubated for 30 mins followed by BzATP addition measured over 180 secs by FLIPR assay Mus musculus 15.85 nM
Antagonist activity at recombinant rat P2X7 expressed in human 1321N1 cells assessed as inhibition of BzATP-induced calcium flux preincubated for 30 mins followed by BzATP addition measured over 180 secs by FLIPR assay Rattus norvegicus 1.549 nM
Antagonist activity at recombinant human P2X7 expressed in human 1321N1 cells assessed as inhibition of BzATP-induced calcium flux preincubated for 30 mins followed by BzATP addition measured over 180 secs by FLIPR assay Homo sapiens 3.467 nM

Cross References

Resources Reference
ChEMBL CHEMBL4079239
DrugBank DB15358
FDA SRS 32524GLF40
PubChem 90409366
SureChEMBL SCHEMBL16036477
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