Daclatasvir (BMS-790052)

Catalog No.S1482

Daclatasvir (BMS-790052) is a highly selective inhibitor of HCV NS5A with EC50 of 9-50 pM, for a broad range of HCV replicon genotypes and the JFH-1 genotype 2a infectious virus in cell culture. Phase 3.

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Daclatasvir (BMS-790052) Chemical Structure

Daclatasvir (BMS-790052) Chemical Structure
Molecular Weight: 738.88

Validation & Quality Control

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Product Information

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Product Description

Biological Activity

Description Daclatasvir (BMS-790052) is a highly selective inhibitor of HCV NS5A with EC50 of 9-50 pM, for a broad range of HCV replicon genotypes and the JFH-1 genotype 2a infectious virus in cell culture. Phase 3.
Targets HCV NS5A [1]
IC50 9 pM-50 pM(EC50)
In vitro BMS-790052 is one of the most potent inhibitors of HCV replication reported so far. The mean EC50 valuses of BMS-790052 are 50 and 9 pM for HCV genotype 1a and 1b replicons, respectively. BMS-790052 displays a therapeutic index (CC50/EC50) of at least 105 and is inactive towards a panel of 10 RNA and DNA viruses, with EC50 higher than 10 μM. This confirms BMS-790052's specificity for HCV. [1] In Huh7 cells harboring the HCV genotype 1b replicons, BMS-790052 blocks both transient and stable HCV genome replication, with EC50 values raging from 1-15 pM. BMS-790052 (100 pM or 1 nM) has been shown to alter the subcellular localization and biochemical fractionation of NS5A. [2] BMS-790052 inhibits hybrid replicons containing HCV genotype-4 NS5A genes with EC50 of 7-13 pM. Residue 30 of NS5A is an important site for BMS-790052-mediated resistance in the hybrid replicons. [3]
In vivo
Features First-in-class, highly selective inhibitor of hepatitis C virus (HCV) NS5A with picomolar EC50 values.

Protocol(Only for Reference)

Kinase Assay: [4]

FRET assay for HCV NS5A inhibitors The peptide (Ac-Asp-Glu-Asp [EDANS]-Glu-Glu-Abu-[COO] Ala-Ser-Lys [DABCYL]-NH2) contains a fluorescence donor {EDANS, 5-[(2-aminoethyl)amino]naphthalene-1-sulfonic acid} near one end of the peptide and an acceptor {DABCYL, 4-[(4-dimethylamino)phenyl]azo)benzoic acid} near the other end. Intermolecular resonance energy transfer between the donor and the acceptor quenches the fluorescence of the peptide, but as the NS3 protease cleaves the peptide, the products are released from resonance energy transfer quenching. The fluorescence of the donor increases over time as more substrate is cleaved by the NS3 protease. The assay reagent is: 5× luciferase cell culture lysis reagent diluted to 1× with dH2O, NaCl (150 mM), the FRET peptide (20 μM). HCV-Huh-7 cells are placed in a 96-well plate, and allowed to attach overnight (1×104 cells per well). The next day, BMS-790052 is added to the wells and the plate is incubated for 72 hours. The plate is then rinsed with PBS and used for the FRET assay by the addition of 30 μL of the FRET peptide assay reagent (described above) per well. Signals are obtained using the Cytofluor 4000 instrument, which has been set to 340 nm (excitation)/490 nm (emission) automatic mode, for 20 cycles or less, with the plate being read in the kinetic mode. Following FRET, 40 μL of luciferase substrate is added to each well and the luciferase is measured.

Cell Assay: [1]

Cell lines HCV replicon cells (Huh7)
Concentrations 0.1 pM - 50 μM, dissolved in DMSO (the final concentration of DMSO is 0.5%)
Incubation Time 72 hours
Method BMS-790052 is added to 96-well plates containing HCV replicon cells seeded approximately 12 hours before in 200 µL media.The cell plates are tested for replication activity and cytotoxicity after 72 hours of incubation. Cytotoxicity is measured with CellTiter-Blue, after which the media and dye are removed, plates are inverted and the remaining liquid is blotted with paper towels. Replication activity of the HCV genotype 1a cell lines is quantified using Renilla luciferase. 1× Renilla luciferase lysis buffer (30 µL) is added to each well and plates are incubated with gentle shaking for 15 min. Renilla luciferase substrate (40 µL) is then added and the signals are detected using a Top Count luminometer set for light emission quantification. One hundred per cent activity is calculated for each cell line for the DMSO-only wells; percentage activity is calculated for each concentration of the inhibitor by dividing the average value for wells containing compound by the average value for wells containing DMSO.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Gao M, et al. Nature, 2010, 465(7294), 96-100.

[2] Lee C, et al. Virology, 2011, 414(1), 10-18.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-06-25)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02762448 Not yet recruiting Hepatitis c Tainan Municipal Hospital June 2016 --
NCT02772744 Not yet recruiting Hepatitis C Zagazig University|Cairo University June 2016 --
NCT02771405 Recruiting Hepatitis C, Chronic|Hepatocellular Carcinoma National Hepatology & Tropical Medicine Research Institut  ...more National Hepatology & Tropical Medicine Research Institute|Cairo University March 2016 Phase 3
NCT02756936 Completed Healthy Genuine Research Center, Egypt|Zeta Pharm Pharmacuetical  ...more Genuine Research Center, Egypt|Zeta Pharm Pharmacuetical Industries, Egypt February 2016 Phase 1
NCT02580474 Recruiting Hepatitis C Myeong Jun Song|Bristol-Myers Squibb|Soonchunhyang Univer  ...more Myeong Jun Song|Bristol-Myers Squibb|Soonchunhyang University Hospital|Dankook University|Chungnam National University Hospital|Konyang University Hospital|Eulji University Hospital|Saint Vincents Hospital, Korea|Konkuk University Hospital|Cheongju St. Marys Hospital, Cheongju, Korea|Severance Hospital|Korea University Guro Hospital|Eulji General Hospital|The Catholic University of Korea February 2016 Phase 4

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Chemical Information

Download Daclatasvir (BMS-790052) SDF
Molecular Weight (MW) 738.88
Formula

C40H50N8O6

CAS No. 1009119-64-5
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms EBP883
Solubility (25°C) * In vitro DMSO 148 mg/mL (200.3 mM)
Ethanol 148 mg/mL (200.3 mM)
Water <1 mg/mL (<1 mM)
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name Carbamic acid, N,N'-[[1,1'-biphenyl]-4,4'-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis-, C,C'-dimethyl ester

Customer Product Validation(3)


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Rating
Source 2011 Dr. Julie Sheldon,Dr Esteban Domingo and Dr Celia Perales. Daclatasvir (BMS-790052) purchased from Selleck
Method Cytotoxic assay
Cell Lines
Concentrations 50 μM
Incubation Time 72 h
Results The 50% cytotoxic concentration (CC50) of BMS-790052 was 14.9 ± 0.6 μM

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Rating
Source 2011 Dr. Anita Nag of Florida State University. Daclatasvir (BMS-790052) purchased from Selleck
Method Western blot
Cell Lines Huh7.5 cells
Concentrations 0-500 pM
Incubation Time 16 h, 40 h
Results BMS-790052 decreased protein expression levels of NS5A in a does- and time-dependent manner.

Click to enlarge
Rating
Source 2011 Dr. Anita Nag of Florida State University. Daclatasvir (BMS-790052) purchased from Selleck
Method Immunofluorescence
Cell Lines JFH-1 cells
Concentrations 0-500 pM
Incubation Time 16 h
Results Cells treated with BMS790052 shows NS5A present in clusters compared to an even cytoplasmic distribution in untreated cells.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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