methyl N-[(2S)-1-[(2S)-2-{5-[4-(4-{2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)phenyl]-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate

• ChemBase ID: 72704
• Molecular Formular: C40H50N8O6
• Molecular Mass: 738.875
• Monoisotopic Mass: 738.38533136
• SMILES: c1cc(ccc1c1cnc([nH]1)[C@H]1N(CCC1)C(=O)[C@H](C(C)C)NC(=O)OC)c1ccc(cc1)c1cnc([nH]1)[C@H]1N(CCC1)C(=O)[C@H](C(C)C)NC(=O)OC
• Canonical SMILES: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc([nH]1)c1ccc(cc1)c1ccc(cc1)c1cnc([nH]1)[C@@H]1CCCN1C(=O)[C@H](C(C)C)NC(=O)OC)C(C)C
• InChI: InChI=1S/C40H50N8O6/c1-23(2)33(45-39(51)53-5)37(49)47-19-7-9-31(47)35-41-21-29(43-35)27-15-11-25(12-16-27)26-13-17-28(18-14-26)30-22-42-36(44-30)32-10-8-20-48(32)38(50)34(24(3)4)46-40(52)54-6/h11-18,21-24,31-34H,7-10,19-20H2,1-6H3,(H,41,43)(H,42,44)(H,45,51)(H,46,52)/t31-,32-,33-,34-/m0/s1
• InChIKey: FKRSSPOQAMALKA-CUPIEXAXSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: methyl N-[(2S)-1-[(2S)-2-{5-[4-(4-{2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)phenyl]-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate
• IUPAC Traditional name: methyl N-[(2S)-1-[(2S)-2-{4-[4-(4-{2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl]pyrrolidin-2-yl]-3H-imidazol-4-yl}phenyl)phenyl]-3H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate
• Synonyms: BMS-790052

Database IDs

• CAS Number: 1214735-16-6
• PubChem SID: 162037625
• PubChem CID: 25154714

CALCULATED PROPERTIES

• Acid pKa: 11.152755
• H Acceptors: 6
• H Donor: 4
• LogD (pH = 5.5): 3.3756588
• LogD (pH = 7.4): 4.1578593
• Log P: 4.1769414
• Molar Refractivity: 201.8188 cm^3
• Polarizability: 82.04871 Å^3
• Polar Surface Area: 174.64 Å^2
• Rotatable Bonds: 13
• Lipinski's Rule of Five: false

PROPERTIES

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: HCV protease

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S1482

Research Area

• Description: Hepatitis C

Biological Activity

• Description: BMS-790052 is a highly selective inhibitor of HCV NS5A with EC50 of 9-50 pM.
• Targets: HCV NS5A
• IC50: 9–50 pM ^[1]
• 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 10^5 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]
• Clinical Trials: BMS-790052 is currently under Phase III clinical trials for treatment of hepatitis C virus (HCV).
• Features: BMS-790052 is a first-in-class, highly selective inhibitor of hepatitis C virus (HCV) NS5A with picomolar EC50 values.

Protocol

• Protocol: 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 (1×10^4 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.
• Protocol: 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
• Methods: 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.

References

• References: [1] Gao M, et al. Nature, 2010, 465(7294), 96-100.
• References: [2] Lee C, et al. Virology, 2011, 414(1), 10-18.
• References: [3] Wang C, et al. Antimicrob Agents Chemother, 2012, 56(3), 1588-1590.
• References: [4] O'Boyle DR 2nd, et al. Antimicrob Agents Chemother, 2005, 49(4), 1346-1353.

REFERENCES

• Gao M, et al. Nature, 2010, 465(7294), 96-100.
• Lee C, et al. Virology, 2011, 414(1), 10-18.
• Wang C, et al. Antimicrob Agents Chemother, 2012, 56(3), 1588-1590.
• O'Boyle DR 2nd, et al. Antimicrob Agents Chemother, 2005, 49(4), 1346-1353.