TMC-647055

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Synonyms
Status
Molecule Category UNKNOWN
UNII 11BD024G7J
EPA CompTox DTXSID90152860

Structure

InChI Key UOBYJVFBFSLCTQ-UHFFFAOYSA-N
Smiles COc1ccc2c(c1)C=C1Cn3c-2c(C2CCCCC2)c2ccc(cc23)C(=O)NS(=O)(=O)N(C)CCOCCN(C)C1=O
InChI
InChI=1S/C32H38N4O6S/c1-34-13-15-42-16-14-35(2)43(39,40)33-31(37)22-9-11-27-28(19-22)36-20-24(32(34)38)17-23-18-25(41-3)10-12-26(23)30(36)29(27)21-7-5-4-6-8-21/h9-12,17-19,21H,4-8,13-16,20H2,1-3H3,(H,33,37)

Physicochemical Descriptors

Property Name Value
Molecular Formula C32H38N4O6S
Molecular Weight 606.75
AlogP 4.16
Hydrogen Bond Acceptor 7.0
Hydrogen Bond Donor 1.0
Number of Rotational Bond 2.0
Polar Surface Area 110.18
Molecular species ACID
Aromatic Rings 3.0
Heavy Atoms 43.0

Bioactivity

Mechanism of Action Action Reference
Hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitor INHIBITOR PubMed
Assay Description Organism Bioactivity Reference
Antiviral activity against Hepatitic C virus genotype 1b clone ET infected in human Huh7 replicon cells after 72 hrs by luciferase reporter gene assay Hepatitis C virus subtype 1b 82.0 nM
Antiviral activity against Hepatitis C virus genotype 6a infected in human HuH7 by transient replicon assay Hepatitis C virus subtype 6a 113.0 nM
Antiviral activity against Hepatitis C virus genotype 4a infected in human HuH7 by transient replicon assay Hepatitis C virus subtype 4a 97.0 nM
Antiviral activity against Hepatitis C virus genotype 3a infected in human HuH7 by transient replicon assay Hepatitis C virus subtype 3a 88.0 nM
Antiviral activity against Hepatitis C virus genotype 1b infected in human HuH7 by transient replicon assay Hepatitis C virus subtype 1b 27.0 nM
Antiviral activity against wild-type Hepatitis C virus Con 1b infected in human HuH7 by transient replicon assay Hepatitis C virus (isolate Con1) 51.0 nM
Antiviral activity against Hepatitis C virus genotype 1a infected in human HuH7 by transient replicon assay Hepatitis C virus subtype 1a 48.0 nM
Binding affinity to Hepatitis C virus genotype 6a NS5B by surface plasmon resonance analysis Hepatitis C virus subtype 6a 30.0 nM
Binding affinity to Hepatitis C virus genotype 5a NS5B by surface plasmon resonance analysis Hepatitis C virus subtype 5a 21.0 nM
Binding affinity to Hepatitis C virus genotype 4a NS5B by surface plasmon resonance analysis Hepatitis C virus subtype 4a 2.0 nM
Binding affinity to Hepatitis C virus genotype 3a NS5B by surface plasmon resonance analysis Hepatitis C virus subtype 3a 6.1 nM
Binding affinity to Hepatitis C virus genotype 2b NS5B by surface plasmon resonance analysis Hepatitis C virus subtype 2b 880.0 nM
Binding affinity to Hepatitis C virus genotype 1b NS5B by surface plasmon resonance analysis Hepatitis C virus subtype 1b 3.9 nM
Binding affinity to Hepatitis C virus genotype 1a NS5B by surface plasmon resonance analysis Hepatitis C virus subtype 1a 7.3 nM
Binding affinity to Hepatitis C virus Con 1b wild-type NS5B by surface plasmon resonance analysis Hepatitis C virus (isolate Con1) 4.1 nM
Antiviral activity against Hepatitis C virus genotype 1a infected in human HuH7-SG cells after 3 days by RT-PCR analysis Hepatitis C virus subtype 1a 166.0 nM
Inhibition of His6-tagged Hepatitis C virus Con 1b NS5B delta21 RNA dependent RNA polymerase expressed in Escherichia coli Rosetta 2 (DE3) after 2 hrs by surface plasmon resonance analysis in presence of 5'-biotinylated rG13 primer Hepatitis C virus (isolate Con1) 34.0 nM
Binding affinity to His6-tagged Hepatitis C virus Con 1b NS5B delta21 RNA dependent RNA polymerase expressed in Escherichia coli Rosetta 2 (DE3) by surface plasmon resonance analysis Hepatitis C virus (isolate Con1) 4.1 nM
Antiviral activity against Hepatitis C virus genotype 1b infected in human HuH7 cells after 72 hrs by luciferase reporter gene assay Hepatitis C virus subtype 1b 77.0 nM
Replicon Assay: The assay utilized the stably transfected cell line Huh-7 luc/neo (hereafter referred to as Huh-Luc). This cell line harbors an RNA encoding a bicistronic expression construct comprising the wild type NS3-NS5B regions of HCV type 1b translated from an Internal Ribosome Entry Site (IRES) from encephalomyocarditis virus (EMCV), preceded by a reporter portion (FfL-luciferase), and a selectable marker portion (neoR, neomycine phosphotransferase). The construct is bordered by 5' and 3' NTRs (non-translated regions) from HCV type 1b. Continued culture of the replicon cells in the presence of G418 (neoR) is dependent on the replication of the HCV RNA. The stably transfected replicon cells that express HCV RNA, which replicates autonomously and to high levels, encoding inter alia luciferase, are used for screening the antiviral compounds. The replicon cells were plated in 384 well plates in the presence of the test and control compounds which were added in various concentrations. Following an incubation of three days, HCV replication was measured by assaying luciferase activity (using standard luciferase assay substrates and reagents and a Perkin Elmer ViewLux™ ultraHTS microplate imager). Replicon cells in the control cultures have high luciferase expression in the absence of any inhibitor. None 70.0 nM
Inhibition Assay: Measurement of HCV NS5B polymerization activity was performed by evaluating the amount of radiolabeled GTP incorporated by the enzyme in a newly synthesized RNA using heteropolymeric RNA template/primer. The RdRp assay was carried out in 384-well plates using 50 nM of purified NS5B enzyme, which was incubated with 300 nM 5'-biotinylated oligo(rG13)/poly(rC) or oligo (rU15)/poly(rA) primer-template, 600 nM of GTP, and 0.1 μCi of [3H]GTP or [3H]UTP in 25 mM Tris-HCl, pH 7.5, 5 mM MgCl2, 25 mM KCl, 17 mM NaCl and 3 mM of DTT. The 30 μL reaction mixture was incubated at room temperature for 2 h before stopping the reaction by adding 30 μL of streptavidin coated SPA-beads (GE Healthcare, Uppsala, Sweden) in 0.5 M EDTA. The 30 μL reaction was terminated after 2 hours at 25° C. upon addition of 30 μl streptavidin-coated SPA beads (GE Healthcare, Uppsala, Sweden 5 mg/ml in 0.5 M EDTA). After incubation at 25° C. for 30 min, the plate was counted using a Packard TopCount microplate reader (30 sec/well, 1 min count delay) and IC50 values were calculated (Table 1: IC50 1bJ4). None 240.0 nM
Primer-Dependent Transcription Assay: IC50 con1b were determined according to the method as described previously (Pauwels et al, 2007, J Virol 81:6909-19) using a primer-dependent transcription assay. Following a 10 minute preincubation with the inhibitor, 20 nM of purified Con1b NS5B enzyme was incubated for 10 min. with 150 nM 5′-biotinylated oligo (rG13) primer, 15 nM poly(rC) template, 19 mM Tris-HCl, 5 mM MgCl2, 17 mM NaCl, 21 mM KCl, and 2.5 mM DTT. 600 nM GTP and 0.13 μCi of [3H]GTP was then added to initiate the 40-μl reaction mixture, which was then incubated at room temperature for 2 h before the reaction was stopped by addition of 40-μl streptavidin-coated SPA beads. None 38.0 nM
Surface Plasmon Resonance (SPR)-Based Assay: All measurements were performed on a Biacore T100 instrument (GE Healthcare). The purified HIS6-tagged NS5BΔC21 polymerases were immobilized using non-covalent capturing to an NTA sensor chip (GE Healthcare) in immobilization buffer (20 mM MOPS pH 7.4, 500 mM NaCl, 0.005% Tween-P20, 1 mM DTT, 50 μM EDTA). Interaction studies were all performed at 25° C. Inhibitors were serially diluted in running buffer (20 mM Tris-HCl pH 7.4, 150 mM NaCl, 50 μM EDTA, 1 mM DTT, 0.005% Tween-P20) containing 5% dimethyl sulfoxide (DMSO). Single-cycle kinetics were used, in which 5 increasing concentrations of compound were injected for a period of 300 s each in 1 single cycle, and dissociation was monitored for a period of 1200 s. The sensor surface was completely regenerated in between the cycles. None 4.4 nM Surface Plasmon Resonance (SPR)-Based Assay: All measurements were performed on a Biacore T100 instrument (GE Healthcare). The purified HIS6-tagged NS5BΔC21 polymerases were immobilized using non-covalent capturing to an NTA sensor chip (GE Healthcare) in immobilization buffer (20 mM MOPS pH 7.4, 500 mM NaCl, 0.005% Tween-P20, 1 mM DTT, 50 μM EDTA). Interaction studies were all performed at 25° C. Inhibitors were serially diluted in running buffer (20 mM Tris-HCl pH 7.4, 150 mM NaCl, 50 μM EDTA, 1 mM DTT, 0.005% Tween-P20) containing 5% dimethyl sulfoxide (DMSO). Single-cycle kinetics were used, in which 5 increasing concentrations of compound were injected for a period of 300 s each in 1 single cycle, and dissociation was monitored for a period of 1200 s. The sensor surface was completely regenerated in between the cycles. None 4.4 nM
Surface Plasmon Resonance (SPR)-Based Assay: All measurements were performed on a Biacore T100 instrument (GE Healthcare). The purified HIS6-tagged NS5BΔC21 polymerases were immobilized using non-covalent capturing to an NTA sensor chip (GE Healthcare) in immobilization buffer (20 mM MOPS pH 7.4, 500 mM NaCl, 0.005% Tween-P20, 1 mM DTT, 50 μM EDTA). Interaction studies were all performed at 25° C. Inhibitors were serially diluted in running buffer (20 mM Tris-HCl pH 7.4, 150 mM NaCl, 50 μM EDTA, 1 mM DTT, 0.005% Tween-P20) containing 5% dimethyl sulfoxide (DMSO). Single-cycle kinetics were used, in which 5 increasing concentrations of compound were injected for a period of 300 s each in 1 single cycle, and dissociation was monitored for a period of 1200 s. The sensor surface was completely regenerated in between the cycles. None 5.2 nM
Surface Plasmon Resonance (SPR)-Based Assay: All measurements were performed on a Biacore T100 instrument (GE Healthcare). The purified HIS6-tagged NS5BΔC21 polymerases were immobilized using non-covalent capturing to an NTA sensor chip (GE Healthcare) in immobilization buffer (20 mM MOPS pH 7.4, 500 mM NaCl, 0.005% Tween-P20, 1 mM DTT, 50 μM EDTA). Interaction studies were all performed at 25° C. Inhibitors were serially diluted in running buffer (20 mM Tris-HCl pH 7.4, 150 mM NaCl, 50 μM EDTA, 1 mM DTT, 0.005% Tween-P20) containing 5% dimethyl sulfoxide (DMSO). Single-cycle kinetics were used, in which 5 increasing concentrations of compound were injected for a period of 300 s each in 1 single cycle, and dissociation was monitored for a period of 1200 s. The sensor surface was completely regenerated in between the cycles. None 5.9 nM
Surface Plasmon Resonance (SPR)-Based Assay: All measurements were performed on a Biacore T100 instrument (GE Healthcare). The purified HIS6-tagged NS5BΔC21 polymerases were immobilized using non-covalent capturing to an NTA sensor chip (GE Healthcare) in immobilization buffer (20 mM MOPS pH 7.4, 500 mM NaCl, 0.005% Tween-P20, 1 mM DTT, 50 μM EDTA). Interaction studies were all performed at 25° C. Inhibitors were serially diluted in running buffer (20 mM Tris-HCl pH 7.4, 150 mM NaCl, 50 μM EDTA, 1 mM DTT, 0.005% Tween-P20) containing 5% dimethyl sulfoxide (DMSO). Single-cycle kinetics were used, in which 5 increasing concentrations of compound were injected for a period of 300 s each in 1 single cycle, and dissociation was monitored for a period of 1200 s. The sensor surface was completely regenerated in between the cycles. None 6.3 nM
Surface Plasmon Resonance (SPR)-Based Assay: All measurements were performed on a Biacore T100 instrument (GE Healthcare). The purified HIS6-tagged NS5BΔC21 polymerases were immobilized using non-covalent capturing to an NTA sensor chip (GE Healthcare) in immobilization buffer (20 mM MOPS pH 7.4, 500 mM NaCl, 0.005% Tween-P20, 1 mM DTT, 50 μM EDTA). Interaction studies were all performed at 25° C. Inhibitors were serially diluted in running buffer (20 mM Tris-HCl pH 7.4, 150 mM NaCl, 50 μM EDTA, 1 mM DTT, 0.005% Tween-P20) containing 5% dimethyl sulfoxide (DMSO). Single-cycle kinetics were used, in which 5 increasing concentrations of compound were injected for a period of 300 s each in 1 single cycle, and dissociation was monitored for a period of 1200 s. The sensor surface was completely regenerated in between the cycles. None 3.9 nM
Surface Plasmon Resonance (SPR)-Based Assay: All measurements were performed on a Biacore T100 instrument (GE Healthcare). The purified HIS6-tagged NS5BΔC21 polymerases were immobilized using non-covalent capturing to an NTA sensor chip (GE Healthcare) in immobilization buffer (20 mM MOPS pH 7.4, 500 mM NaCl, 0.005% Tween-P20, 1 mM DTT, 50 μM EDTA). Interaction studies were all performed at 25° C. Inhibitors were serially diluted in running buffer (20 mM Tris-HCl pH 7.4, 150 mM NaCl, 50 μM EDTA, 1 mM DTT, 0.005% Tween-P20) containing 5% dimethyl sulfoxide (DMSO). Single-cycle kinetics were used, in which 5 increasing concentrations of compound were injected for a period of 300 s each in 1 single cycle, and dissociation was monitored for a period of 1200 s. The sensor surface was completely regenerated in between the cycles. None 2.2 nM
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging Homo sapiens -3.67 %
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate Severe acute respiratory syndrome coronavirus 2 15.14 %
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging Chlorocebus sabaeus 0.66 % Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging Chlorocebus sabaeus 0.66 %
Antiviral activity against HCV Hepatitis C virus 82.0 nM

Related Entries

Cross References

Resources Reference
ChEMBL CHEMBL2043025
DrugBank DB11822
FDA SRS 11BD024G7J
PubChem 44556044
SureChEMBL SCHEMBL1239667
ZINC ZINC000084726167
CONTENTS