lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC(F)(F)CC1
InChIKey: XUCXIMYTIQZZHZ-UHFFFAOYSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 445.5, ALogP 4.52, HBA 4, HBD 1, PSA 72.47, QED 0.67
Compound (SMILES): O=C(NS(=O)(=O)N1CCC1)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
InChIKey: LATHVTUYKGMIPI-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q15858
Assay: Radioligand Binding Assay: Radioligand Binding Studies: Saturation experiments. A representative compound of formula (I) was tritiated. Three tritiums were incorporated in place of methyl hydrogens to generate [3H]compound. Binding of this radioligand was preformed in 5 mL borosilicate glass test tubes at room temperature. Binding was initiated by adding membranes to increasing concentrations of [3H]compound in 100 mM NaCl, 20 mM Tris HCl, pH 7.4 buffer containing 0.01% w/v bovine serum albumin (BSA) for 18 h. Non-specific binding was determined in the presence of 1 uM unlabelled compound. After 18 h, the reactants were filtered through GF/C glass fiber filters presoaked in 0.5% w/v polyethylene imine. Filters were washed with 15 mL ice cold 100 mM NaCl, 20 mM Tris HCl, pH7.4 buffer containing 0.25% BSA to separate bound from free ligand. [3H]compound bound to filters was quantified by liquid scintillation counting.Competitive binding experiments.
Measurement: IC50 = 290 nM (pChEMBL 6.539999961853027)
Descriptors: MW 445.59, ALogP 3.23, HBA 5, HBD 1, PSA 88.6, QED 0.7
Compound (SMILES): O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F
InChIKey: YXSMNJJREGDZRE-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q15858
Assay: Radioligand Binding Assay: Radioligand Binding Studies: Saturation experiments. A representative compound of formula (I) was tritiated. Three tritiums were incorporated in place of methyl hydrogens to generate [3H]compound. Binding of this radioligand was preformed in 5 mL borosilicate glass test tubes at room temperature. Binding was initiated by adding membranes to increasing concentrations of [3H]compound in 100 mM NaCl, 20 mM Tris HCl, pH 7.4 buffer containing 0.01% w/v bovine serum albumin (BSA) for 18 h. Non-specific binding was determined in the presence of 1 uM unlabelled compound. After 18 h, the reactants were filtered through GF/C glass fiber filters presoaked in 0.5% w/v polyethylene imine. Filters were washed with 15 mL ice cold 100 mM NaCl, 20 mM Tris HCl, pH7.4 buffer containing 0.25% BSA to separate bound from free ligand. [3H]compound bound to filters was quantified by liquid scintillation counting.Competitive binding experiments.
Measurement: IC50 = 11 nM (pChEMBL 7.960000038146973)
Descriptors: MW 458.5, ALogP 3.59, HBA 4, HBD 1, PSA 75.71, QED 0.68
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC2(CC1)CC2
InChIKey: GFDXIUXAFNREKM-UHFFFAOYSA-N
Target: Sodium channel protein type 8 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UQD0
Assay: Inhibition of human Nav1.6 expressed in HEK293 cells by electrophysiology assay
Measurement: IC50 = 38 nM (pChEMBL 7.420000076293945)
Descriptors: MW 435.56, ALogP 4.66, HBA 4, HBD 1, PSA 72.47, QED 0.68
Compound (SMILES): CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
InChIKey: KSBYUWHBUZLDDL-UHFFFAOYSA-N
Target: Sodium channel protein type 7 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q01118
Assay: Inhibition of human Nav1.7 expressed in HEK293 cells incubated for 1 hr in presence of veratridine by sodium influx assay
Measurement: IC50 = 23 nM (pChEMBL 7.639999866485596)
Descriptors: MW 508.62, ALogP 4.49, HBA 5, HBD 1, PSA 75.71, QED 0.46
Compound (SMILES): CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCCCC2)cc1F
InChIKey: MTOFVXVDNHJZIU-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q15858
Assay: Inhibition of human Nav1.7 alpha subunit expressed in HEK293 cells co-expressing beta1 subunit at -60 mV holding potential by whole-cell patch voltage clamp electrophysiology recording
Measurement: IC50 = 43 nM (pChEMBL 7.369999885559082)
Descriptors: MW 363.84, ALogP 3.13, HBA 4, HBD 1, PSA 72.47, QED 0.87
Compound (SMILES): CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F
InChIKey: IKSUDZQUQOMVKP-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q15858
Assay: Radioligand Binding Assay: Radioligand Binding Studies: Saturation experiments. A representative compound of formula (I) was tritiated. Three tritiums were incorporated in place of methyl hydrogens to generate [3H]compound. Binding of this radioligand was preformed in 5 mL borosilicate glass test tubes at room temperature. Binding was initiated by adding membranes to increasing concentrations of [3H]compound in 100 mM NaCl, 20 mM Tris HCl, pH 7.4 buffer containing 0.01% w/v bovine serum albumin (BSA) for 18 h. Non-specific binding was determined in the presence of 1 uM unlabelled compound. After 18 h, the reactants were filtered through GF/C glass fiber filters presoaked in 0.5% w/v polyethylene imine. Filters were washed with 15 mL ice cold 100 mM NaCl, 20 mM Tris HCl, pH7.4 buffer containing 0.25% BSA to separate bound from free ligand. [3H]compound bound to filters was quantified by liquid scintillation counting.Competitive binding experiments.
Measurement: IC50 = 15.5 nM (pChEMBL 7.809999942779541)
Descriptors: MW 369.46, ALogP 3.35, HBA 4, HBD 1, PSA 72.47, QED 0.83
Compound (SMILES): Cc1ccc(COc2ccc3nc(C4CCCC[C@@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)nc1
InChIKey: RPNGLHUBZFJLRE-CGAIIQECSA-N
Target: Arachidonate 5-lipoxygenase-activating protein (SINGLE PROTEIN), Homo sapiens
UniProt: P20292
Assay: Binding Assay: The assay below is used to test the modulatory activity of compounds against FLAP. Human and mouse FLAP-encoding DNA was amplified by polymerase chain reaction and cloned into pFastBac1 (Invitrogen) with a NH2-terminal 6-His tag for expression in Spodoptera frugiperda (Sf-9) cells. FLAP-containing membranes were prepared as was a FITC-labeled FLAP modulator (3-(3-(tert-butylthio)-1-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropanoic acid). The FLAP binding assay is performed in HTRF format (homogeneous time resolved fluorescence). FLAP-containing membranes (1 μg/well final for human) are incubated in the presence of the HTRF ligand, [5-[({[2-(2-{3-[3-(tert-butylsulfanyl)-1-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropanoyl}hydrazino)-2-oxoethyl]sulfanyl}acetyl)amino]-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid] (25 nM final), a terbium labeled anti-His tag antibody (0.5 ng/well final, from Cisbio) and compounds.
Measurement: Ki = 390 nM (pChEMBL 6.409999847412109)
Descriptors: MW 534.45, ALogP 6.49, HBA 5, HBD 1, PSA 77.24, QED 0.29
Compound (SMILES): C#C[C@@H]1CN(C(=O)[C@H](CC(C)C)NC(=O)c2ccc(-c3csc(N4CCN(C)CC4)n3)cc2)[C@@H]2C(=O)CO[C@H]12
InChIKey: FIJFMUKDMVGIOK-ZRYIBQHNSA-N
Target: Procathepsin L (SINGLE PROTEIN), Homo sapiens
UniProt: P07711
Assay: Biological Assay (Test 1): Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically H-D-Ala-Leu-Lys-AMC, and were determined in either 100 mM Mes/Tris, pH 7.0 containing 1 mM EDTA and 10 mM 2-mercaptoethanol or 100 mMNa phosphate, imM EDTA, 0.1% PEG4000 pH 6.5 or 100 mM Na acetate, pH 5.5 containing 5 mM EDTA and 20 mM cysteine, in each case optionally with 1M DTT as stabiliser. The enzyme concentration used was 5 nM. The stock substrate solution was prepared at 10 mM in DMSO. Screens were carried out at a fixed substrate concentration of 60 uM and detailed kinetic studies with doubling dilutions of substrate from 250 uM. The total DMSO concentration in the assay was kept below 3%. All assays were conducted at ambient temperature. Product fluorescence (excitation at 390 nm, emission at 460 nm) was monitored with a Labsystems Fluoroskan Ascent fluorescent plate reader. The first test compound prepared in DMSO is added to column 1 of the top row.
Measurement: Ki = 3000.5 nM (pChEMBL 5.519999980926514)
Descriptors: MW 549.7, ALogP 2.13, HBA 8, HBD 1, PSA 95.08, QED 0.53
Compound (SMILES): C#C[C@@H]1CN(C(=O)[C@H](CC(C)C)NC(=O)c2ccc(-c3nc(N4CCN(C)CC4)sc3F)cc2)[C@@H]2C(=O)CO[C@H]12
InChIKey: HUMYXJUMFCJTGM-KWACHACRSA-N
Target: Procathepsin L (SINGLE PROTEIN), Homo sapiens
UniProt: P07711
Assay: Biological Assay (Test 1): Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically H-D-Ala-Leu-Lys-AMC, and were determined in either 100 mM Mes/Tris, pH 7.0 containing 1 mM EDTA and 10 mM 2-mercaptoethanol or 100 mMNa phosphate, imM EDTA, 0.1% PEG4000 pH 6.5 or 100 mM Na acetate, pH 5.5 containing 5 mM EDTA and 20 mM cysteine, in each case optionally with 1M DTT as stabiliser. The enzyme concentration used was 5 nM. The stock substrate solution was prepared at 10 mM in DMSO. Screens were carried out at a fixed substrate concentration of 60 uM and detailed kinetic studies with doubling dilutions of substrate from 250 uM. The total DMSO concentration in the assay was kept below 3%. All assays were conducted at ambient temperature. Product fluorescence (excitation at 390 nm, emission at 460 nm) was monitored with a Labsystems Fluoroskan Ascent fluorescent plate reader. The first test compound prepared in DMSO is added to column 1 of the top row.
Measurement: Ki = 3000.5 nM (pChEMBL 5.519999980926514)
Descriptors: MW 567.69, ALogP 2.27, HBA 8, HBD 1, PSA 95.08, QED 0.51
Compound (SMILES): CCC(CC)n1ncc2c(=O)[nH]c(CC3CCCCC3)nc21
InChIKey: GXWSVMJGLJNVHK-UHFFFAOYSA-N
Target: cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B (SINGLE PROTEIN), Homo sapiens
UniProt: Q13370
Assay: In Vitro Inhibition Assay: The test substances are dissolved in 100% DMSO and serially diluted to determine their in vitro effect on PDE 9A. 2 uL portions of the diluted substance solutions are introduced into the wells of microtiter plates (Isoplate; Wallac Inc., Atlanta, Ga.). Then 50 uL of a dilution of the PDE9A preparation described above are added. The dilution of the PDE9A preparation is chosen so that less than 70% of the substrate is converted during the subsequent incubation (typical dilution: 1:10000; dilution buffer: 50 mM Tris/HCl pH 7.5, 8.3 mM MgCl2, 1.7 mM EDTA, 0.2% BSA). The substrate, [8-3H] guanosine 3',5'-cyclic phosphate (1 uCi/uL; Amersham Pharmacia Biotech., Piscataway, N.J.) is diluted 1:2000 with assay buffer (50 mM Tris/HCl pH 7.5, 8.3 mM MgCl2, 1.7 mM EDTA) to a concentration of 0.0005 uCi/uL.
Measurement: IC50 > 4000 nM (pChEMBL 5.3979997634887695)
Descriptors: MW 302.42, ALogP 3.6, HBA 4, HBD 1, PSA 63.57, QED 0.92
Compound (SMILES): CCc1cc(C(N)=O)ccc1-n1nc(C(C)C)c2c(-n3cnc(-c4cnn(C)c4)c3)ccnc21
InChIKey: NVVPMZUGELHVMH-UHFFFAOYSA-N
Target: Heat shock protein HSP 90-beta (SINGLE PROTEIN), Homo sapiens
UniProt: P08238
Assay: Inhibition of FITC-geldanamycin binding to recombinant human HSP90beta expressed in Escherichia coli preincubated for 2 hrs followed by Geldanamycin-FITC addition and measured after 5 hrs by fluorescence polarization competitive binding assay
Measurement: Ki = 21.3 nM (pChEMBL 7.670000076293945)
Descriptors: MW 454.54, ALogP 3.79, HBA 8, HBD 1, PSA 109.44, QED 0.42
Compound (SMILES): COc1cccc(-c2ccc3nccc(Nc4cccc5[nH]ncc45)c3c2)c1
InChIKey: IKXJOEAHXPIXTE-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: Kinase Assay: Inhibition of kinase activity by test compound disclosed herein was estimated by quantifying the amount of [33P] incorporation of substrate in the presence of test compound. Standard assay conditions were 2 ng of recombinant C-Raf or 5 ng of recombinant B-Raf or 5 ng of recombinant B-Raf (V600E) kinase (Upstate Biotechnology) with 500 ng MEK1(K97R) in assay buffer {8 μM ATP, 0.5 μCi [33P]ATP (specific activity 3000 Ci/mmol, PerkinElmer), 50 mM Tris/HCl (pH7.5), and 1 mM EGTA, 1 mM Na3VO4, 1% 2-mercaptoethanol, 0.1% Brij 35, and 0.2 mg/ml BSA} at a final volume of 25 μL. Reactions were incubated at 30° C. for 30 min and stopped by adding 3% phosphoric acid, harvested onto a 96-well GF/B UniFilter (PerkinElmer) using a unifilter harvester (PerkinElmer), and counted with a TopCount microplate scintillation counter (PerkinElmer). The IC50 values of inhibitors were determined after carrying out assays at 3-fold serially diluted concentrations of each compound in duplication.
Measurement: IC50 = 426 nM (pChEMBL 6.369999885559082)
Descriptors: MW 366.42, ALogP 5.53, HBA 4, HBD 2, PSA 62.83, QED 0.44
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC(F)(F)CC1
InChIKey: XUCXIMYTIQZZHZ-UHFFFAOYSA-N
Target: Cytochrome P450 1A2 (SINGLE PROTEIN), Homo sapiens
UniProt: P05177
Assay: Inhibition of CYP1A2 (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 445.5, ALogP 4.52, HBA 4, HBD 1, PSA 72.47, QED 0.67
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC2(CC1)CC2
InChIKey: GFDXIUXAFNREKM-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Mus musculus
UniProt: Q62205
Assay: Inhibition of mouse Nav1.7 expressed in HEK293 cells by electrophysiology assay
Measurement: IC50 = 2.2 nM (pChEMBL 8.65999984741211)
Descriptors: MW 435.56, ALogP 4.66, HBA 4, HBD 1, PSA 72.47, QED 0.68
Compound (SMILES): CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
InChIKey: KSBYUWHBUZLDDL-UHFFFAOYSA-N
Target: Sodium channel protein type 5 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q14524
Assay: Inhibition of human Nav1.5 expressed in HEK293 cells incubated for 1 hr in presence of veratridine and anthropleurin-C by sodium influx assay
Measurement: IC50 = 1100 nM (pChEMBL 5.960000038146973)
Descriptors: MW 508.62, ALogP 4.49, HBA 5, HBD 1, PSA 75.71, QED 0.46
Compound (SMILES): CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F
InChIKey: IKSUDZQUQOMVKP-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q15858
Assay: Radioligand Binding Assay: Radioligand Binding Studies: Saturation experiments. A representative compound of formula (I) was tritiated. Three tritiums were incorporated in place of methyl hydrogens to generate [3H]compound. Binding of this radioligand was preformed in 5 mL borosilicate glass test tubes at room temperature. Binding was initiated by adding membranes to increasing concentrations of [3H]compound in 100 mM NaCl, 20 mM Tris HCl, pH 7.4 buffer containing 0.01% w/v bovine serum albumin (BSA) for 18 h. Non-specific binding was determined in the presence of 1 uM unlabelled compound. After 18 h, the reactants were filtered through GF/C glass fiber filters presoaked in 0.5% w/v polyethylene imine. Filters were washed with 15 mL ice cold 100 mM NaCl, 20 mM Tris HCl, pH7.4 buffer containing 0.25% BSA to separate bound from free ligand. [3H]compound bound to filters was quantified by liquid scintillation counting.Competitive binding experiments.
Measurement: IC50 = 6 nM (pChEMBL 8.220000267028809)
Descriptors: MW 369.46, ALogP 3.35, HBA 4, HBD 1, PSA 72.47, QED 0.83
Compound (SMILES): Cc1ccc(COc2ccc3nc(C4CCCC[C@@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)nc1
InChIKey: RPNGLHUBZFJLRE-CGAIIQECSA-N
Target: Arachidonate 5-lipoxygenase-activating protein (SINGLE PROTEIN), Homo sapiens
UniProt: P20292
Assay: Binding Assay: The assay below is used to test the modulatory activity of compounds against FLAP. Human and mouse FLAP-encoding DNA was amplified by polymerase chain reaction and cloned into pFastBac1 (Invitrogen) with a NH2-terminal 6-His tag for expression in Spodoptera frugiperda (Sf-9) cells. FLAP-containing membranes were prepared as was a FITC-labeled FLAP modulator (3-(3-(tert-butylthio)-1-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropanoic acid). The FLAP binding assay is performed in HTRF format (homogeneous time resolved fluorescence). FLAP-containing membranes (1 μg/well final for human) are incubated in the presence of the HTRF ligand, [5-[({[2-(2-{3-[3-(tert-butylsulfanyl)-1-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropanoyl}hydrazino)-2-oxoethyl]sulfanyl}acetyl)amino]-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid] (25 nM final), a terbium labeled anti-His tag antibody (0.5 ng/well final, from Cisbio) and compounds.
Measurement: Ki = 2.2 nM (pChEMBL 8.65999984741211)
Descriptors: MW 534.45, ALogP 6.49, HBA 5, HBD 1, PSA 77.24, QED 0.29
Compound (SMILES): C#C[C@@H]1CN(C(=O)[C@H](CC(C)C)NC(=O)c2ccc(-c3csc(N4CCN(C)CC4)n3)cc2)[C@@H]2C(=O)CO[C@H]12
InChIKey: FIJFMUKDMVGIOK-ZRYIBQHNSA-N
Target: Cathepsin S (SINGLE PROTEIN), Homo sapiens
UniProt: P25774
Assay: Cathepsin S Ki Determination: The assay uses baculovirus-expressed human cathepsin S and the boc-Val-Leu-Lys-AMC fluorescent substrate available from Bachem in a 384 well plate format, in which 7 test compounds can be tested in parallel with a positive control comprising a known cathepsin S inhibitor comparator.
Measurement: Ki = 20500 nM (pChEMBL 4.690000057220459)
Descriptors: MW 549.7, ALogP 2.13, HBA 8, HBD 1, PSA 95.08, QED 0.53
Compound (SMILES): C#C[C@@H]1CN(C(=O)[C@H](CC(C)C)NC(=O)c2ccc(-c3csc(N4CCN(C)CC4)n3)c(F)c2)[C@@H]2C(=O)CO[C@H]12
InChIKey: RFCUHPQJTGIXFS-GTKJVGNCSA-N
Target: Cathepsin S (SINGLE PROTEIN), Homo sapiens
UniProt: P25774
Assay: Cathepsin S Ki Determination: The assay uses baculovirus-expressed human cathepsin S and the boc-Val-Leu-Lys-AMC fluorescent substrate available from Bachem in a 384 well plate format, in which 7 test compounds can be tested in parallel with a positive control comprising a known cathepsin S inhibitor comparator.
Measurement: Ki = 20500 nM (pChEMBL 4.690000057220459)
Descriptors: MW 567.69, ALogP 2.27, HBA 8, HBD 1, PSA 95.08, QED 0.51
Compound (SMILES): CCC(CC)n1ncc2c(=O)[nH]c(CC3CCCCC3)nc21
InChIKey: GXWSVMJGLJNVHK-UHFFFAOYSA-N
Target: High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A (SINGLE PROTEIN), Homo sapiens
UniProt: O60658
Assay: In Vitro Inhibition Assay: The test substances are dissolved in 100% DMSO and serially diluted to determine their in vitro effect on PDE 9A. 2 uL portions of the diluted substance solutions are introduced into the wells of microtiter plates (Isoplate; Wallac Inc., Atlanta, Ga.). Then 50 uL of a dilution of the PDE9A preparation described above are added. The dilution of the PDE9A preparation is chosen so that less than 70% of the substrate is converted during the subsequent incubation (typical dilution: 1:10000; dilution buffer: 50 mM Tris/HCl pH 7.5, 8.3 mM MgCl2, 1.7 mM EDTA, 0.2% BSA). The substrate, [8-3H] guanosine 3',5'-cyclic phosphate (1 uCi/uL; Amersham Pharmacia Biotech., Piscataway, N.J.) is diluted 1:2000 with assay buffer (50 mM Tris/HCl pH 7.5, 8.3 mM MgCl2, 1.7 mM EDTA) to a concentration of 0.0005 uCi/uL.
Measurement: IC50 > 4000 nM (pChEMBL 5.3979997634887695)
Descriptors: MW 302.42, ALogP 3.6, HBA 4, HBD 1, PSA 63.57, QED 0.92
Compound (SMILES): CCc1cc(C(N)=O)ccc1-n1nc(C(C)C)c2c(-n3cnc(-c4cnn(C)c4)c3)ccnc21
InChIKey: NVVPMZUGELHVMH-UHFFFAOYSA-N
Target: Endoplasmin (SINGLE PROTEIN), Homo sapiens
UniProt: P14625
Assay: Inhibition of FITC-geldanamycin binding to N-terminal His-tagged recombinant human GRP94 expressed in Escherichia coli preincubated for 2 hrs followed by Geldanamycin-FITC addition and measured after 5 hrs by fluorescence polarization competitive binding assay
Measurement: Ki > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 454.54, ALogP 3.79, HBA 8, HBD 1, PSA 109.44, QED 0.42
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC(F)(F)CC1
InChIKey: XUCXIMYTIQZZHZ-UHFFFAOYSA-N
Target: Cytochrome P450 2C19 (SINGLE PROTEIN), Homo sapiens
UniProt: P33261
Assay: Inhibition of CYP2C19 (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 445.5, ALogP 4.52, HBA 4, HBD 1, PSA 72.47, QED 0.67
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC2(CC1)CC2
InChIKey: GFDXIUXAFNREKM-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Rattus norvegicus
UniProt: O08562
Assay: Inhibition of rat Nav1.7 expressed in HEK293 cells by electrophysiology assay
Measurement: IC50 = 3.7 nM (pChEMBL 8.430000305175781)
Descriptors: MW 435.56, ALogP 4.66, HBA 4, HBD 1, PSA 72.47, QED 0.68
Compound (SMILES): CCC(CC)n1ncc2c(=O)[nH]c(CC3CCCCC3)nc21
InChIKey: GXWSVMJGLJNVHK-UHFFFAOYSA-N
Target: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A (SINGLE PROTEIN), Homo sapiens
UniProt: Q9Y233
Assay: In Vitro Inhibition Assay: The test substances are dissolved in 100% DMSO and serially diluted to determine their in vitro effect on PDE 9A. 2 uL portions of the diluted substance solutions are introduced into the wells of microtiter plates (Isoplate; Wallac Inc., Atlanta, Ga.). Then 50 uL of a dilution of the PDE9A preparation described above are added. The dilution of the PDE9A preparation is chosen so that less than 70% of the substrate is converted during the subsequent incubation (typical dilution: 1:10000; dilution buffer: 50 mM Tris/HCl pH 7.5, 8.3 mM MgCl2, 1.7 mM EDTA, 0.2% BSA). The substrate, [8-3H] guanosine 3',5'-cyclic phosphate (1 uCi/uL; Amersham Pharmacia Biotech., Piscataway, N.J.) is diluted 1:2000 with assay buffer (50 mM Tris/HCl pH 7.5, 8.3 mM MgCl2, 1.7 mM EDTA) to a concentration of 0.0005 uCi/uL.
Measurement: IC50 > 4000 nM (pChEMBL 5.3979997634887695)
Descriptors: MW 302.42, ALogP 3.6, HBA 4, HBD 1, PSA 63.57, QED 0.92
Compound (SMILES): CCc1cc(C(N)=O)ccc1-n1nc(C(C)C)c2c(-n3cnc(-c4cnn(C)c4)c3)ccnc21
InChIKey: NVVPMZUGELHVMH-UHFFFAOYSA-N
Target: Heat shock protein 75 kDa, mitochondrial (SINGLE PROTEIN), Homo sapiens
UniProt: Q12931
Assay: Inhibition of FITC-geldanamycin binding to N-terminal His-tagged recombinant human TRAP1 (60 to 704 residues) expressed in Escherichia coli preincubated for 2 hrs followed by Geldanamycin-FITC addition and measured after 5 hrs by fluorescence polarization competitive binding assay
Measurement: Ki > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 454.54, ALogP 3.79, HBA 8, HBD 1, PSA 109.44, QED 0.42
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC(F)(F)CC1
InChIKey: XUCXIMYTIQZZHZ-UHFFFAOYSA-N
Target: Cytochrome P450 2C9 (SINGLE PROTEIN), Homo sapiens
UniProt: P11712
Assay: Inhibition of CYP2C9 (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 445.5, ALogP 4.52, HBA 4, HBD 1, PSA 72.47, QED 0.67
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC2(CC1)CC2
InChIKey: GFDXIUXAFNREKM-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q15858
Assay: Displacement of [3H]GX-545 from human Nav1.7 alpha subunit expressed in HEK293 cells co-expressing beta1 subunit by liquid scintillation counting analysis
Measurement: IC50 = 15 nM (pChEMBL 7.820000171661377)
Descriptors: MW 435.56, ALogP 4.66, HBA 4, HBD 1, PSA 72.47, QED 0.68
Compound (SMILES): CCC(CC)n1ncc2c(=O)[nH]c(CC3CCCCC3)nc21
InChIKey: GXWSVMJGLJNVHK-UHFFFAOYSA-N
Target: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (SINGLE PROTEIN), Homo sapiens
UniProt: O76083
Assay: In Vitro Inhibition Assay: The test substances are dissolved in 100% DMSO and serially diluted to determine their in vitro effect on PDE 9A. 2 uL portions of the diluted substance solutions are introduced into the wells of microtiter plates (Isoplate; Wallac Inc., Atlanta, Ga.). Then 50 uL of a dilution of the PDE9A preparation described above are added. The dilution of the PDE9A preparation is chosen so that less than 70% of the substrate is converted during the subsequent incubation (typical dilution: 1:10000; dilution buffer: 50 mM Tris/HCl pH 7.5, 8.3 mM MgCl2, 1.7 mM EDTA, 0.2% BSA). The substrate, [8-3H] guanosine 3',5'-cyclic phosphate (1 uCi/uL; Amersham Pharmacia Biotech., Piscataway, N.J.) is diluted 1:2000 with assay buffer (50 mM Tris/HCl pH 7.5, 8.3 mM MgCl2, 1.7 mM EDTA) to a concentration of 0.0005 uCi/uL.
Measurement: IC50 = 110 nM (pChEMBL 6.960000038146973)
Descriptors: MW 302.42, ALogP 3.6, HBA 4, HBD 1, PSA 63.57, QED 0.92
Compound (SMILES): CCc1cc(C(N)=O)ccc1-n1nc(C(C)C)c2c(-n3cnc(-c4cnn(C)c4)c3)ccnc21
InChIKey: NVVPMZUGELHVMH-UHFFFAOYSA-N
Target: Heat shock protein HSP 90-alpha (SINGLE PROTEIN), Homo sapiens
UniProt: P07900
Assay: Binding affinity to human HSP90-alpha N-terminal domain assessed as dissociation constant at 100 uM at 25 degC by isothermal titration calorimetry
Measurement: Kd = 170 nM (pChEMBL 6.769999980926514)
Descriptors: MW 454.54, ALogP 3.79, HBA 8, HBD 1, PSA 109.44, QED 0.42
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC(F)(F)CC1
InChIKey: XUCXIMYTIQZZHZ-UHFFFAOYSA-N
Target: Cytochrome P450 2D6 (SINGLE PROTEIN), Homo sapiens
UniProt: P10635
Assay: Inhibition of CYP2D6 (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 445.5, ALogP 4.52, HBA 4, HBD 1, PSA 72.47, QED 0.67
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC2(CC1)CC2
InChIKey: GFDXIUXAFNREKM-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q15858
Assay: Inhibition of human Nav1.7 alpha subunit expressed in HEK293 cells co-expressing beta1 subunit at -60 mV holding potential by whole-cell patch voltage clamp electrophysiology recording
Measurement: IC50 = 0.6 nM (pChEMBL 9.220000267028809)
Descriptors: MW 435.56, ALogP 4.66, HBA 4, HBD 1, PSA 72.47, QED 0.68
Compound (SMILES): CCC(CC)n1ncc2c(=O)[nH]c(CC3CCCCC3)nc21
InChIKey: GXWSVMJGLJNVHK-UHFFFAOYSA-N
Target: Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (SINGLE PROTEIN), Homo sapiens
UniProt: Q9HCR9
Assay: Inhibition Assay: The test substances are dissolved in 100% DMSO and serially diluted to determine their in vitro effect on PDE 9A. Typically, serial dilutions from 200 uM to 1.6 uM are prepared (resulting final concentrations in the assay: 4 uM to 0.032 uM). 2 uL portions of the diluted substance solutions are introduced into the wells of microtiter plates (Isoplate; Wallac Inc., Atlanta, Ga.). Then 50 uL of a dilution of the PDE9A preparation described above are added. The dilution of the PDE9A preparation is chosen so that less than 70% of the substrate is converted during the subsequent incubation (typical dilution: 1:10000; dilution buffer: 50 mM Tris/HCl pH 7.5, 8.3 mM MgCl2, 1.7 mM EDTA, 0.2% BSA). The substrate, [8-3H] guanosine 3',5'-cyclic phosphate (1 uCi/uL; Amersham Pharmacia Biotech., Piscataway, N.J.) is diluted 1:2000 with assay buffer (50 mM Tris/HCl pH 7.5, 8.3 mM MgCl2, 1.7 mM EDTA) to a concentration of 0.0005 uCi/uL.
Measurement: IC50 > 4000 nM (pChEMBL 5.3979997634887695)
Descriptors: MW 302.42, ALogP 3.6, HBA 4, HBD 1, PSA 63.57, QED 0.92
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC(F)(F)CC1
InChIKey: XUCXIMYTIQZZHZ-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Mus musculus
UniProt: Q62205
Assay: Inhibition of mouse Nav1.7 at -60 mV holding potential by PatchXpress automated voltage clamp electrophysiology technique
Measurement: IC50 = 2.5 nM (pChEMBL 8.600000381469727)
Descriptors: MW 445.5, ALogP 4.52, HBA 4, HBD 1, PSA 72.47, QED 0.67
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC2(CC1)CC2
InChIKey: GFDXIUXAFNREKM-UHFFFAOYSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 435.56, ALogP 4.66, HBA 4, HBD 1, PSA 72.47, QED 0.68
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC(F)(F)CC1
InChIKey: XUCXIMYTIQZZHZ-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Rattus norvegicus
UniProt: O08562
Assay: Inhibition of rat Nav1.7 at -60 mV holding potential by PatchXpress automated voltage clamp electrophysiology technique
Measurement: IC50 = 9 nM (pChEMBL 8.050000190734863)
Descriptors: MW 445.5, ALogP 4.52, HBA 4, HBD 1, PSA 72.47, QED 0.67
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC2(CC1)CC2
InChIKey: GFDXIUXAFNREKM-UHFFFAOYSA-N
Target: Cytochrome P450 1A2 (SINGLE PROTEIN), Homo sapiens
UniProt: P05177
Assay: Inhibition of CYP1A2 (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 435.56, ALogP 4.66, HBA 4, HBD 1, PSA 72.47, QED 0.68
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC(F)(F)CC1
InChIKey: XUCXIMYTIQZZHZ-UHFFFAOYSA-N
Target: Sodium channel protein type 5 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q14524
Assay: Inhibition of human Nav1.5 alpha subunit expressed in HEK293 cells co-expressing beta1 subunit at -60 mV holding potential by PatchXpress automated voltage clamp electrophysiology technique
Measurement: IC50 = 260 nM (pChEMBL 6.579999923706055)
Descriptors: MW 445.5, ALogP 4.52, HBA 4, HBD 1, PSA 72.47, QED 0.67
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC2(CC1)CC2
InChIKey: GFDXIUXAFNREKM-UHFFFAOYSA-N
Target: Cytochrome P450 2C19 (SINGLE PROTEIN), Homo sapiens
UniProt: P33261
Assay: Inhibition of CYP2C19 (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 435.56, ALogP 4.66, HBA 4, HBD 1, PSA 72.47, QED 0.68
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC(F)(F)CC1
InChIKey: XUCXIMYTIQZZHZ-UHFFFAOYSA-N
Target: Sodium channel protein type 2 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q99250
Assay: Inhibition of human Nav1.2 alpha subunit expressed in HEK293 cells co-expressing beta1 subunit at -35 mV holding potential by PatchXpress automated voltage clamp electrophysiology technique
Measurement: IC50 = 6 nM (pChEMBL 8.220000267028809)
Descriptors: MW 445.5, ALogP 4.52, HBA 4, HBD 1, PSA 72.47, QED 0.67
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC2(CC1)CC2
InChIKey: GFDXIUXAFNREKM-UHFFFAOYSA-N
Target: Cytochrome P450 2C9 (SINGLE PROTEIN), Homo sapiens
UniProt: P11712
Assay: Inhibition of CYP2C9 (unknown origin)
Measurement: IC50 = 6100 nM (pChEMBL 5.210000038146973)
Descriptors: MW 435.56, ALogP 4.66, HBA 4, HBD 1, PSA 72.47, QED 0.68
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC(F)(F)CC1
InChIKey: XUCXIMYTIQZZHZ-UHFFFAOYSA-N
Target: Sodium channel protein type 1 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: P35498
Assay: Inhibition of human Nav1.1 alpha subunit expressed in HEK293 cells co-expressing beta1 subunit at -40 mV holding potential by PatchXpress automated voltage clamp electrophysiology technique
Measurement: IC50 = 48 nM (pChEMBL 7.320000171661377)
Descriptors: MW 445.5, ALogP 4.52, HBA 4, HBD 1, PSA 72.47, QED 0.67
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC2(CC1)CC2
InChIKey: GFDXIUXAFNREKM-UHFFFAOYSA-N
Target: Cytochrome P450 2D6 (SINGLE PROTEIN), Homo sapiens
UniProt: P10635
Assay: Inhibition of CYP2D6 (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 435.56, ALogP 4.66, HBA 4, HBD 1, PSA 72.47, QED 0.68
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC(F)(F)CC1
InChIKey: XUCXIMYTIQZZHZ-UHFFFAOYSA-N
Target: Sodium channel protein type 8 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UQD0
Assay: Inhibition of human Nav1.6 alpha subunit expressed in HEK293 cells co-expressing beta1 subunit at -35 mV holding potential by PatchXpress automated voltage clamp electrophysiology technique
Measurement: IC50 = 49 nM (pChEMBL 7.309999942779541)
Descriptors: MW 445.5, ALogP 4.52, HBA 4, HBD 1, PSA 72.47, QED 0.67
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC2(CC1)CC2
InChIKey: GFDXIUXAFNREKM-UHFFFAOYSA-N
Target: Sodium channel protein type 10 subunit alpha (SINGLE PROTEIN), Mus musculus
UniProt: Q6QIY3
Assay: Inhibition of TTX-resistant Nav1.8 in mouse dorsal root ganglion neuron by voltage clamp recording
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 435.56, ALogP 4.66, HBA 4, HBD 1, PSA 72.47, QED 0.68
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC(F)(F)CC1
InChIKey: XUCXIMYTIQZZHZ-UHFFFAOYSA-N
Target: Sodium channel protein type 10 subunit alpha (SINGLE PROTEIN), Mus musculus
UniProt: Q6QIY3
Assay: Inhibition of TTX-resistant Nav1.8 in mouse dorsal root ganglion neuron by voltage clamp recording
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 445.5, ALogP 4.52, HBA 4, HBD 1, PSA 72.47, QED 0.67
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC2(CC1)CC2
InChIKey: GFDXIUXAFNREKM-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q15858
Assay: Electrophysiological Assay: Patch voltage clamp electrophysiology allows for the direct measurement and quantification of block of voltage-gated sodium channels (NaV's), and allows the determination of the time- and voltage-dependence of block which has been interpreted as differential binding to the resting, open, and inactivated states of the sodium channel (Hille, B., Journal of General Physiology (1977), 69: 497-515).The following patch voltage clamp electrophysiology studies were performed on representative compounds of the invention using human embryonic kidney cells (HEK), permanently transfected with an expression vector containing the full-length cDNA coding for the desired human sodium channel alpha -subunit, grown in culture media containing 10% FBS, 1% PSG, and 0.5 mg/mL G418 at 37 C. with 5% CO2. HEK cells used for the electrophysiology (EP) recordings had a passage number of less than 40 for all studies and were used within three days from the time of plating.
Measurement: IC50 = 4 nM (pChEMBL 8.399999618530273)
Descriptors: MW 435.56, ALogP 4.66, HBA 4, HBD 1, PSA 72.47, QED 0.68
Compound (SMILES): CC1(COc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)CCC2(CC1)CC2
InChIKey: GFDXIUXAFNREKM-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q15858
Assay: Radioligand Binding Assay: Radioligand Binding Studies: Saturation experiments. A representative compound of formula (I) was tritiated. Three tritiums were incorporated in place of methyl hydrogens to generate [3H]compound. Binding of this radioligand was preformed in 5 mL borosilicate glass test tubes at room temperature. Binding was initiated by adding membranes to increasing concentrations of [3H]compound in 100 mM NaCl, 20 mM Tris HCl, pH 7.4 buffer containing 0.01% w/v bovine serum albumin (BSA) for 18 h. Non-specific binding was determined in the presence of 1 uM unlabelled compound. After 18 h, the reactants were filtered through GF/C glass fiber filters presoaked in 0.5% w/v polyethylene imine. Filters were washed with 15 mL ice cold 100 mM NaCl, 20 mM Tris HCl, pH7.4 buffer containing 0.25% BSA to separate bound from free ligand. [3H]compound bound to filters was quantified by liquid scintillation counting.Competitive binding experiments.
Measurement: IC50 = 3 nM (pChEMBL 8.520000457763672)
Descriptors: MW 435.56, ALogP 4.66, HBA 4, HBD 1, PSA 72.47, QED 0.68
Compound (SMILES): COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(C)CC6)C[C@H]5/C=C\CCCCN(C)C(=O)[C@@H]4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
InChIKey: LYPMUUHUNIGEOB-OTVJIGPHSA-N
Target: Hepatitis C virus serine protease, NS3/NS4A (PROTEIN COMPLEX), Hepatitis C virus
UniProt: A3EZI9
Assay: Enzymatic Assay: The aim of this in vitro assay was to measure the inhibition of HCV NS3/4A protease complexes by the compounds of the present invention. This assay provides an indication of how effective compounds of the present invention would be in inhibiting HCV NS3/4A proteolytic activity. The inhibition of full-length hepatitis C NS3 protease enzyme was measured essentially as described in Poliakov, 2002 Prot Expression & Purification 25 363 371. Briefly, the hydrolysis of a depsipeptide substrate,Â  Ac-DED(Edans)EEAbuÃ[COO]ASK(Dabcyl)-NH2 (AnaSpec, San Jose, USA), was measured spectrofluorometrically in the presence of a peptide cofactor, KKGSVVIVGRIVLSGK (Ã¢ Â«ke Engstrom, Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden). [Landro, 1997 #Biochem 36 9340-9348].
Measurement: Ki = 0.3 nM (pChEMBL 9.520000457763672)
Descriptors: MW 784.4, ALogP 5.99, HBA 10, HBD 2, PSA 156.89, QED 0.26
Compound (SMILES): COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(C)CC6)C[C@H]5/C=C\CCCCN(C)C(=O)[C@@H]4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
InChIKey: CVFQOKIBZTWREC-UDWBKMJLSA-N
Target: Hepatitis C virus serine protease, NS3/NS4A (PROTEIN COMPLEX), Hepatitis C virus
UniProt: A3EZI9
Assay: Enzymatic Assay: The aim of this in vitro assay was to measure the inhibition of HCV NS3/4A protease complexes by the compounds of the present invention. This assay provides an indication of how effective compounds of the present invention would be in inhibiting HCV NS3/4A proteolytic activity. The inhibition of full-length hepatitis C NS3 protease enzyme was measured essentially as described in Poliakov, 2002 Prot Expression & Purification 25 363 371. Briefly, the hydrolysis of a depsipeptide substrate,Â  Ac-DED(Edans)EEAbuÃ[COO]ASK(Dabcyl)-NH2 (AnaSpec, San Jose, USA), was measured spectrofluorometrically in the presence of a peptide cofactor, KKGSVVIVGRIVLSGK (Ã¢ Â«ke Engstrom, Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden). [Landro, 1997 #Biochem 36 9340-9348].
Measurement: Ki = 0.25 nM (pChEMBL 9.600000381469727)
Descriptors: MW 763.98, ALogP 5.64, HBA 10, HBD 2, PSA 156.89, QED 0.28
Compound (SMILES): Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCC(=O)NC1
InChIKey: KPYXZOZRPALMPX-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase pim-1 (SINGLE PROTEIN), Homo sapiens
UniProt: P11309
Assay: Homogeneous Time Resolved Fluorescence Assay (HTRF): The assay for the determination of Pim activity is based on the formation of phosphorylated biotinylated-BAD peptide at the Serine 112 residue (S112) and employs HTRF® (homogeneous time resolved fluorescence) technology to detect the product in a 96-well plate format. The phosphorylation of biotinylated-BAD (S112) peptide by full length recombinant Pim-1, Pim-2, or Pim-3 protein was detected with streptavidin:Allophycocyanin (APC) conjugate and a europium (Eu) labeled antibody directed against phosphorylated-BAD (S112). Excitation of Eu by a high energy laser light (337 nm) leads to a transfer of energy to the APC molecule, and results in an emission at 665 nm. The fluorescence is directly proportional to the amount of phosphorylated BAD peptide present in the reaction. Compounds were prepared in DMSO by conducting 3-fold serial dilutions to give a 10-point dosing curve having a high dose of 1 μM. A reference compound was included on each assay plate in order to validate that plate; on one plate of every assay run, two additional reference compounds were included. The final buffer conditions were as follows: 60 mM Hepes, pH 7.0, 0.05% BSA, 2 mM DTT. Incubations were carried out at RT (22° C.) for 2 h for Pim-1, 1 hour and 30 min for Pim-3, and 45 min for Pim-2. The reaction was stopped by the addition of 3 mM EDTA, and fluorescence was measured by an HTRF® Rubystar microplate reader.
Measurement: IC50 = 28.2 nM (pChEMBL 7.550000190734863)
Descriptors: MW 390.45, ALogP 1.91, HBA 5, HBD 4, PSA 111.8, QED 0.55
Compound (SMILES): CCOc1ccc(CC(=O)O)cc1-c1ccc(F)c2c1CN(C(=O)CC1COCc3ccccc31)CC2
InChIKey: VBDREJSPASEEAM-UHFFFAOYSA-N
Target: Prostaglandin D2 receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9Y5Y4
Assay: Radioligand Displacement Assay: Binding assay was performed in a final assay volume of 250 ul. First, 25 ul of test compound, previously diluted in Binding-Buffer (Binding-Buffer: 50 mM Tris-Base, 100 mM NaCl, 1 mM EDTA, 0.1% BSA (protease free), 0.01% NaN3, 10 mM MnCl2, pH 7.0) was placed into each well. After addition of 75 ul Binding-Buffer, 50 ul of the radioligand 3H-PGD2 (at 2.5 nM (220.000 dpm/well) from ANAWA ART0662) was added to each well. Binding assay was started by addition of 100 ul CRTH2 membrane fragments, reaching a final concentration of 20 ug/well. For non-specific binding, PGD2 was added to the reaction mixture to 10 mM final concentration. This assay mix was incubated for 90 minutes at room temperature and then filtered through a GF/C filter 96-well plate which was pre-soaked for 3 hours in 0.5% polyethyleneimine (PEI). The filter-wells were washed three times with ice cold Binding-Buffer. Then, 40 ul of Microscint-40 (Packard) was added to each well and the retained radioactivity quantified in a Topcount (Packard).
Measurement: IC50 = 3.4 nM (pChEMBL 8.470000267028809)
Descriptors: MW 503.57, ALogP 5.11, HBA 4, HBD 1, PSA 76.07, QED 0.49
Compound (SMILES): O=C1NCCn2cc(-c3cccc4ccc(Nc5cccnc5)nc34)cc21
InChIKey: CMJKTDGFDREUGD-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase pim-1 (SINGLE PROTEIN), Homo sapiens
UniProt: P11309
Assay: Homogeneous Time Resolved Fluorescence Assay (HTRF): The assay for the determination of Pim activity is based on the formation of phosphorylated biotinylated-BAD peptide at the Serine 112 residue (S112) and employs HTRF® (homogeneous time resolved fluorescence) technology to detect the product in a 96-well plate format. The phosphorylation of biotinylated-BAD (S112) peptide by full length recombinant Pim-1, Pim-2, or Pim-3 protein was detected with streptavidin:Allophycocyanin (APC) conjugate and a europium (Eu) labeled antibody directed against phosphorylated-BAD (S112). Excitation of Eu by a high energy laser light (337 nm) leads to a transfer of energy to the APC molecule, and results in an emission at 665 nm. The fluorescence is directly proportional to the amount of phosphorylated BAD peptide present in the reaction. Compounds were prepared in DMSO by conducting 3-fold serial dilutions to give a 10-point dosing curve having a high dose of 1 μM. A reference compound was included on each assay plate in order to validate that plate; on one plate of every assay run, two additional reference compounds were included. The final buffer conditions were as follows: 60 mM Hepes, pH 7.0, 0.05% BSA, 2 mM DTT. Incubations were carried out at RT (22° C.) for 2 h for Pim-1, 1 hour and 30 min for Pim-3, and 45 min for Pim-2. The reaction was stopped by the addition of 3 mM EDTA, and fluorescence was measured by an HTRF® Rubystar microplate reader.
Measurement: IC50 = 1.1 nM (pChEMBL 8.960000038146973)
Descriptors: MW 355.4, ALogP 3.59, HBA 5, HBD 2, PSA 71.84, QED 0.59
Compound (SMILES): COC(=O)c1ccc(C#Cc2c(N)ncnc2N[C@@H](C)c2nc3cccc(Cl)c3c(=O)n2-c2ccccc2)nc1
InChIKey: QAPXWOUFBKTNEH-KRWDZBQOSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay: PI3K isoforms were assayed under initial rate conditions in the presence of 25 mM Hepes (pH 7.4), and 2xKm ATP (100-300 uM), 10 uM PIP2, 5% glycerol, 5 mM MgCl2, 50 mM NaCl, 0.05% (v/v) Chaps, 1 mM dithiothreitol, 1% (v/v) DMSO at the following concentrations for each isoform: PI3K alpha, beta, delta, and gamma at 50 picomolar (pM) and PI3Kgamma at 2 nanomolar (nM). After an assay reaction time of 30 minutes at 25° C., reactions were terminated with a final concentration of 10 mM EDTA, 10 nM labeled-PIP3, and 35 nM Europium labeled GRP-1 detector protein before reading TR-FRET on an Envision plate reader (Ex: 340 nm; Em: 615/665 nm; 100 us delay and 500 us read window).
Measurement: IC50 > 1000 nM (pChEMBL 6)
Descriptors: MW 551.99, ALogP 4.17, HBA 10, HBD 2, PSA 137.91, QED 0.24
Compound (SMILES): CN1CCC(Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCN(CC5=C(c6ccc(Cl)cc6)CC(C)(C)CC5)CC4)cc3Oc3ccc4[nH]ncc4c3)cc2[N+](=O)[O-])CC1
InChIKey: WCRURXUMEIPECW-UHFFFAOYSA-N
Target: Apoptosis regulator Bcl-2 (SINGLE PROTEIN), Mus musculus
UniProt: P10417
Assay: Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) Assay: The inhibition constant (Ki) is the dissociation constant of an enzyme-inhibitor complex or a protein/small molecule complex, wherein the small molecule is inhibiting binding of one protein to another protein or peptide. Where the Ki for a compound is represented as > (greater than) a certain numerical value, it is intended to mean that the binding affinity value (e.g., for Bcl-XL) is greater than the limits of detection of the assay used. Where the binding selectivity ratio for a compound is represented as > (greater than) a certain numerical value, it is intended to mean that the selectivity of a particular compound for Bcl-2 over Bcl-XL is at least as great as the number indicated. Where the Ki for a compound is represented as < (less than) a certain numerical value, it is intended to mean that the binding affinity value (e.g., for Bcl-2) is lower than the limit of detection of the assay used. Inhibition constants were determined using Wang's equation (Wang Z-X).
Measurement: Ki = 5.428 nM (pChEMBL 8.270000457763672)
Descriptors: MW 867.47, ALogP 8.33, HBA 11, HBD 3, PSA 166.04, QED 0.08
Compound (SMILES): CCNC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc(N5CCN(C(C)=O)CC5)cc4OC)ncc3F)c(OC)c2)CC1
InChIKey: RKPVNBGYUZVHDT-UHFFFAOYSA-N
Target: ALK tyrosine kinase receptor (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UM73
Assay: Homogeneous Time-resolved fluorescence (HTRF) Assay: In order to measure the inhibitory activity against ALK, a Grainer 96-well round type bottom plate was added with the compounds (2 μl) prepared in Examples 1 to 89, and mixed with ALK enzyme (1 ul) and a peptide substrate (2 μl) with biotin attached thereto for 15 minutes and cultured thereafter. Here, ATP solution (5 μl) was added thereto and kinase reaction was performed at room temperature for 30 minutes. XL 665 (5 μl), to which Streptavidin dissolved in ethylenediaminetetraacetic acid solution was attached, anti-phosphotyrosine antibody (5 μl), to which europium (Eu3+) was attached, were added to a reaction solution to stop the reaction, cultured for 1 hour, and analyzed using Homogeneous Time-resolved fluorescence (HTRF, Cisbio). The result was read by a Wallac Envision 2103 device at the wavelength range of 615/665 nm.
Measurement: IC50 = 31 nM (pChEMBL 7.510000228881836)
Descriptors: MW 621.72, ALogP 3.64, HBA 10, HBD 3, PSA 127.43, QED 0.33
Compound (SMILES): C[C@@H]1CN(Cc2ccccc2)c2nc(F)ccc2[C@H](C)N1C(=O)NCc1ccccc1
InChIKey: JWDSGJQAZOIVIJ-MOPGFXCFSA-N
Target: Voltage-dependent T-type calcium channel subunit alpha-1G (SINGLE PROTEIN), Homo sapiens
UniProt: O43497
Assay: Channel blocking activity at recombinant human CaV 3.1 channel expressed in HEK293 cells assessed as inhibition of Ca2+ flux preincubated for 3 mins followed by CaCl2 addition by fluo-4 dye-based FLIPR assay
Measurement: IC50 = 7 nM (pChEMBL 8.149999618530273)
Descriptors: MW 418.52, ALogP 4.9, HBA 3, HBD 1, PSA 48.47, QED 0.61
Compound (SMILES): O=C1Cc2ccc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)Nc4ncns4)cc3F)cc2N1
InChIKey: VLOASXUDBRPQJN-UHFFFAOYSA-N
Target: Sodium channel protein type 9 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q15858
Assay: Electrophysiological Assay (In vitro Assay): Patch voltage clamp electrophysiology allows for the direct measurement and quantification of block of voltage-gated sodium channels (Nav's), and allows the determination of the time- and voltage-dependence of block which has been interpreted as differential binding to the resting, open, and inactivated states of the sodium channel (Hille, B., Journal of General Physiology (1977), 69: 497-515).The following patch voltage clamp electrophysiology studies were performed on representative compounds of the invention using human embryonic kidney cells (HEK), permanently transfected with an expression vector containing the full-length cDNA coding for the desired human sodium channel α-subunit, grown in culture media containing 10% FBS, 1% PSG, and 0.5 mg/mL G418 at 37° C. with 5% CO2. HEK cells used for the electrophysiology (EP) recordings had a passage number of less than 40 for all studies and were used within three days from the time of plating. Nav1.7 and Nav1.5 cDNAs (NM_00297
Measurement: IC50 = 1 nM (pChEMBL 9)
Descriptors: MW 534.95, ALogP 5.22, HBA 7, HBD 2, PSA 110.28, QED 0.35