SIMEPREVIR

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Synonyms
Status
Molecule Category Free-form
ATC J05AP05
UNII 9WS5RD66HZ

Structure

InChI Key JTZZSQYMACOLNN-VDWJNHBNSA-N
Smiles COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6CC6)C[C@H]5/C=C\CCCCN(C)C(=O)[C@@H]4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
InChI
InChI=1S/C38H47N5O7S2/c1-21(2)30-20-51-35(40-30)29-18-32(26-13-14-31(49-5)22(3)33(26)39-29)50-24-16-27-28(17-24)36(45)43(4)15-9-7-6-8-10-23-19-38(23,41-34(27)44)37(46)42-52(47,48)25-11-12-25/h8,10,13-14,18,20-21,23-25,27-28H,6-7,9,11-12,15-17,19H2,1-5H3,(H,41,44)(H,42,46)/b10-8-/t23-,24-,27-,28-,38-/m1/s1

Physicochemical Descriptors

Property Name Value
Molecular Formula C38H47N5O7S2
Molecular Weight 749.96
AlogP 5.25
Hydrogen Bond Acceptor 10.0
Hydrogen Bond Donor 2.0
Number of Rotational Bond 8.0
Polar Surface Area 156.89
Molecular species ACID
Aromatic Rings 3.0
Heavy Atoms 52.0
Assay Description Organism Bioactivity Reference
Inhibition of recombinant full length HCV NS3/4A protease Hepatitis C virus 0.36 nM
Antiviral activity against HCV in human Huh7 cells assessed as luciferase activity Hepatitis C virus 7.8 nM
Inhibition of HCV NS3 protease by FRET assay Hepatitis C virus 0.36 nM
Antiviral activity against HCV 1B infected in human Huh7 cells by firefly luciferase reporter gene assay Hepatitis C virus subtype 1b 7.8 nM
Antiviral activity against HCV 1b infected in human Huh-7 cells after 48hrs by luciferase assay Hepatitis C virus subtype 1b 1.4 nM
Antiviral activity against HCV 1a infected in human Huh-7 cells after 48hrs by luciferase assay Hepatitis C virus subtype 1a 2.3 nM
Inhibition of HCV 1a NS3/4A protease by FRET assay Hepatitis C virus subtype 1a 10.0 nM
Inhibition of HCV 1a H77 NS3/4A protease using RetS1 as a substrate by fluorescence resonance energy transfer cleavage assay Hepatitis C virus subtype 1a 0.5 nM
Inhibition of HCV 1b isolate con1 NS3/4A protease using RetS1 as a substrate by fluorescence resonance energy transfer cleavage assay Hepatitis C virus 0.4 nM
Inhibition of human cathepsin S in human JY cells assessed as p10 accumulation by fluorescence-based assay Homo sapiens 800.0 nM
Antiviral activity against Hepatitis C virus 1b infected in human HuH7 cells assessed as viral RNA level after 72 hrs by luciferase reporter gene assay Hepatitis C virus subtype 1b 8.1 nM
Antiviral activity against Hepatitis C virus 1b infected in human HuH7 cells assessed as viral RNA level after 72 hrs by quantitative reverse transcriptase PCR Hepatitis C virus subtype 1b 13.0 nM
Antiviral activity against Hepatitis C virus 1b isolate con1 infected in human HuH7 cells assessed as viral RNA level after 72 hrs by quantitative reverse transcriptase PCR Hepatitis C virus 25.2 nM
Antiviral activity against HCV 1a H77 infected in human HuH7 cells assessed as viral RNA level after 72 hrs by quantitative reverse transcriptase PCR Hepatitis C virus subtype 1a 28.4 nM
Antiviral activity against Hepatitis C virus in presence of 1 mg/ml alpha-1 acid glycoprotein Hepatitis C virus 11.4 nM
Antiviral activity against Hepatitis C virus in presence of 40 mg/ml human serum albumin Hepatitis C virus 14.1 nM
Antiviral activity against Hepatitis C virus in presence of 1 mg/ml alpha-1 acid glycoprotein and 40 mg/ml human serum albumin Hepatitis C virus 14.6 nM
Antiviral activity against Hepatitis C virus in presence of 40% human serum Hepatitis C virus 11.2 nM
Ratio of EC50 Hepatitis C virus in presence of 1 mg/ml AAG to EC50 for Hepatitis C virus in presence of 10% FCS Hepatitis C virus 1.4 nM
Ratio of EC50 Hepatitis C virus in presence of 40 mg/ml HAS to EC50 for Hepatitis C virus in presence of 10% FCS Hepatitis C virus 1.7 nM
Ratio of EC50 Hepatitis C virus in presence of 1 mg/ml AAG and 40 mg/ml HAS to EC50 for Hepatitis C virus in presence of 10% FCS Hepatitis C virus 1.8 nM
Ratio of EC50 Hepatitis C virus in presence of 40% human serum to EC50 for Hepatitis C virus in presence of 10% FCS Hepatitis C virus 1.4 nM
Inhibition of Hepatitis C virus subtype 1a NS3/4A protease Hepatitis C virus subtype 1a 0.4 nM
Inhibition of Hepatitis C virus subtype 1b NS3/4A protease Hepatitis C virus subtype 1b 0.5 nM
Antiviral activity against Hepatitis C virus subtype 1b infected in HuH7 cells after 72 hrs by luciferase reporter gene assay Hepatitis C virus subtype 1b 8.0 nM
Inhibition of Hepatitis C virus subtype 2a NS3/4A protease Hepatitis C virus subtype 2a 13.0 nM
Inhibition of Hepatitis C virus subtype 4a NS3/4A protease Hepatitis C virus subtype 3a 13.0 nM
Inhibition of Hepatitis C virus subtype 5a NS3/4A protease Hepatitis C virus subtype 4a 13.0 nM
Inhibition of Hepatitis C virus subtype 6a NS3/4A protease Hepatitis C virus subtype 5a 13.0 nM
Inhibition of Hepatitis C virus subtype 3a NS3/4A protease Hepatitis C virus subtype 6a 37.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing WT NS3 infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 11.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 V36L mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 18.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 V36M mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 20.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 V36A mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 34.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q41R mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 18.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 F43S mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 83.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 F43I mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 562.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 F43V mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 626.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 T54A mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 5.9 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 T54S mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 5.4 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80R mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 49.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80H mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 41.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80K mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 62.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80G mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 22.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80L mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 12.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R109K mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 11.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 S138T mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 77.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R155M mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 3.5 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R155I mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 6.6 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R155Q mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 21.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R155T mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 314.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R155K mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 260.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R155G mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 350.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 A156S mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 3.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 A156G mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 206.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 A156T mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 377.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168G mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 42.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168N mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 79.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168E mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 302.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 V170T mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 52.0 nM
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 V170A mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay Hepatitis C virus subtype 1b 22.0 nM
Antiviral activity against HCV1b Con1 harboring NS3 protease gene infected in human Huh7/Lunet cells assessed as inhibition of viral replication after 3 days by luciferase based transient-transfection assay Hepatitis C virus 3.3 nM
Antiviral activity against HCV1b harboring Q80Q polymorphism in NS3 protease gene infected in human Huh7/Lunet cells assessed as inhibition of viral replication after 3 days by luciferase based transient-transfection assay Hepatitis C virus subtype 1b 2.7 nM
Antiviral activity against HCV1b harboring Q80K polymorphism in NS3 protease gene infected in human Huh7/Lunet cells assessed as inhibition of viral replication after 3 days by luciferase based transient-transfection assay Hepatitis C virus subtype 1b 20.1 nM
Antiviral activity against HCV1b by cell based replicon assay Hepatitis C virus subtype 1b 25.0 nM
Antiviral activity against HCV1a by cell based replicon assay Hepatitis C virus subtype 1a 28.0 nM
Inhibition of HCV 1a NS3 protease Hepatitis C virus subtype 1a 0.5 nM
Inhibition of HCV 1b NS3 protease Hepatitis C virus subtype 1b 0.4 nM
Antiviral activity against HCV subtype 1b expressing NS3/4A R115K mutant protease infected in ET cells after 72 hrs Hepatitis C virus subtype 1b 56.0 nM
Antiviral activity against HCV subtype 1b expressing NS3/4A D168V mutant protease infected in ET cells after 72 hrs Hepatitis C virus subtype 1b 140.0 nM
Antiviral activity against HCV subtype 1b expressing NS3/4A D168A mutant protease infected in ET cells after 72 hrs Hepatitis C virus subtype 1b 149.0 nM
Antiviral activity against HCV subtype 1b expressing NS3/4A A156V mutant protease infected in ET cells after 72 hrs Hepatitis C virus subtype 1b 344.0 nM
Antiviral activity against HCV subtype 1b expressing NS3/4A A156T mutant protease infected in ET cells after 72 hrs Hepatitis C virus subtype 1b 86.0 nM
Antiviral activity against HCV subtype 1b expressing NS3/4A A156S mutant protease infected in ET cells after 72 hrs Hepatitis C virus subtype 1b 0.3 nM
Antiviral activity against HCV subtype 1b expressing wild type NS3/4A protease infected in ET cells after 72 hrs Hepatitis C virus subtype 1b 1.0 nM
Antiviral activity against HCV subtype 1b infected in human hepatoma cells Hepatitis C virus subtype 1b 1.0 nM
Antiviral activity against HCV subtype 1a infected in human hepatoma cells Hepatitis C virus subtype 1a 2.0 nM
Inhibition of HCV subtype 1a NS3/4A protease (Ac-DE-Dap(QXL520)-EE-Abu-psi-[COO]-ASC(5-FAMsp)-NH2 as substrate by FRET analysis Hepatitis C virus subtype 1a 10.0 nM
Antiviral activity against Hepatitis C virus genotype 1b Con 1 infected in Huh7-replicon cells assessed as decrease in HCV replicon RNA level by qRT-PCR analysis Hepatitis C virus (isolate Con1) 25.0 nM
Antiviral activity against Hepatitis C virus genotype 1a H77 infected in Huh7-replicon cells assessed as decrease in HCV replicon RNA level by qRT-PCR analysis Hepatitis C virus (isolate H77) 28.0 nM
Antiviral activity against Hepatitis C virus genotype 1b infected in Huh7-clone ET Rep cells assessed as inhibition of HCV replication by luciferase assay Hepatitis C virus subtype 1b 7.8 nM
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease Hepatitis C virus subtype 1b 1.4 nM
Inhibition of Hepatitis C virus genotype 1a full-length NS3/4A protease Hepatitis C virus subtype 1a 0.36 nM
Inhibition of HCV genotype 1a NS3/4A protease using Ac-DED(Edans)EEAbu-psi[COO]ASK(Dabcyl)-NH2 as substrate by FRET assay Hepatitis C virus subtype 1a 0.36 nM
Antiviral activity against HCV genotype 1a Hepatitis C virus subtype 1a 7.8 nM
Inhibition Assay: 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, Ac-DED(Edans)EEAbu[COO]ASK(Dabcyl)-NH2 (AnaSpec, San Jose, USA), was measured spectrofluorometrically in the presence of a peptide cofactor, KKGSVVIVGRIVLSGK (Ake Engstrom, Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden). [Landro, 1997 #Biochem 36 9340-9348]. The enzyme (1 nM) was incubated in 50 mM HEPES, pH 7.5, 10 mM DTT, 40% glycerol, 0.1% n-octyl-D-glucoside, with 25 μM NS4A cofactor and inhibitor at 30 C. for 10 min, whereupon the reaction was initiated by addition of 0.5 μM substrate. Inhibitors were dissolved in DMSO, sonicated for 30 sec. and vortexed. Hepatitis C virus 0.5 nM
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,  Ac-DED(Edans)EEAbuÏ[COO]ASK(Dabcyl)-NH2 (AnaSpec, San Jose, USA), was measured spectrofluorometrically in the presence of a peptide cofactor, KKGSVVIVGRIVLSGK (â «ke Engstrom, Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden). [Landro, 1997 #Biochem 36 9340-9348]. Hepatitis C virus 0.5 nM
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate Severe acute respiratory syndrome coronavirus 2 -47.67 %
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 1.85 % 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 1.85 %
Inhibition of HCV NS3/4a protease Hepatitis C virus 99.9 %
Antiviral activity against HCV J6/JFH/JC1 harboring D168V mutant infected in human Huh7.5 cells assessed as inhibition of viral replication measured after 72 hrs by qRT-PCR analysis Hepatitis C virus 930.0 nM
Antiviral activity against wild-type HCV J6/JFH/JC1 infected in human Huh7.5 cells assessed as inhibition of viral replication measured after 72 hrs by qRT-PCR analysis Hepatitis C virus 40.0 nM

Cross References

Resources Reference
ChEBI 134743
ChEMBL CHEMBL501849
DrugBank DB06290
DrugCentral 4812
FDA SRS 9WS5RD66HZ
Guide to Pharmacology 7367
PDB 30B
PubChem 24873435
SureChEMBL SCHEMBL826061
ZINC ZINC000085540268
CONTENTS