|
Inhibition of HCV NS3 protease by FRET assay
|
Hepatitis C virus
|
0.25
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Hepatitis C virus NS3 protease inhibitors comprising a novel aromatic P1 moiety.
Year : 2008
Volume : 16
Issue : 6
First Page : 2955
Last Page : 2967
Authors : Rönn R, Lampa A, Peterson SD, Gossas T, Akerblom E, Danielson UH, Karlén A, Sandström A.
Abstract : Inhibition of the hepatitis C virus (HCV) NS3 protease has emerged as an attractive approach to defeat the global hepatitis C epidemic. In this work, we present the synthesis and biochemical evaluation of HCV NS3 protease inhibitors comprising a non-natural aromatic P(1) moiety. A series of inhibitors with aminobenzoyl sulfonamides displaying submicromolar potencies in the full-length NS3 protease assay was prepared through a microwave-irradiated, palladium-catalyzed, amidocarbonylation protocol.
|
Antiviral activity against Hepatitis C virus infected human hepatoma cells by replicon assay
|
Hepatitis C virus
|
2.1
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Hepatitis C virus NS3 protease inhibitors comprising a novel aromatic P1 moiety.
Year : 2008
Volume : 16
Issue : 6
First Page : 2955
Last Page : 2967
Authors : Rönn R, Lampa A, Peterson SD, Gossas T, Akerblom E, Danielson UH, Karlén A, Sandström A.
Abstract : Inhibition of the hepatitis C virus (HCV) NS3 protease has emerged as an attractive approach to defeat the global hepatitis C epidemic. In this work, we present the synthesis and biochemical evaluation of HCV NS3 protease inhibitors comprising a non-natural aromatic P(1) moiety. A series of inhibitors with aminobenzoyl sulfonamides displaying submicromolar potencies in the full-length NS3 protease assay was prepared through a microwave-irradiated, palladium-catalyzed, amidocarbonylation protocol.
|
Inhibition of HCV NS3 protease by FRET assay
|
Hepatitis C virus
|
0.25
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents.
Year : 2010
Volume : 18
Issue : 14
First Page : 5413
Last Page : 5424
Authors : Lampa A, Ehrenberg AE, Gustafsson SS, Vema A, Kerblom E, Lindeberg G, Karlén A, Danielson UH, Sandström A.
Abstract : Phenylglycine has proved to be a useful P2 residue in HCV NS3 protease inhibitors. A novel pi-pi-interaction between the phenylglycine and the catalytic H57 residue of the protease is postulated. We hypothesized that the introduction of a vinyl on the phenylglycine might strengthen this pi-pi-interaction. Thus, herein is presented the synthesis and inhibitory potency of a series of acyclic vinylated phenylglycine-based HCV NS3 protease inhibitors. Surprisingly, inhibitors based on both D- and L-phenylglycine were found to be effective inhibitors, with a slight preference for the d-epimers. Furthermore, prime-side alkenylic extension of the C-terminal acylsulfonamide group gave significantly improved inhibitors with potencies in the nanomolar range (approximately 35 nM), potencies which were retained on mutant variants of the protease.
|
Antiviral activity against HCV 1B infected in human Huh7 cells by firefly luciferase reporter gene assay
|
Hepatitis C virus subtype 1b
|
2.1
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents.
Year : 2010
Volume : 18
Issue : 14
First Page : 5413
Last Page : 5424
Authors : Lampa A, Ehrenberg AE, Gustafsson SS, Vema A, Kerblom E, Lindeberg G, Karlén A, Danielson UH, Sandström A.
Abstract : Phenylglycine has proved to be a useful P2 residue in HCV NS3 protease inhibitors. A novel pi-pi-interaction between the phenylglycine and the catalytic H57 residue of the protease is postulated. We hypothesized that the introduction of a vinyl on the phenylglycine might strengthen this pi-pi-interaction. Thus, herein is presented the synthesis and inhibitory potency of a series of acyclic vinylated phenylglycine-based HCV NS3 protease inhibitors. Surprisingly, inhibitors based on both D- and L-phenylglycine were found to be effective inhibitors, with a slight preference for the d-epimers. Furthermore, prime-side alkenylic extension of the C-terminal acylsulfonamide group gave significantly improved inhibitors with potencies in the nanomolar range (approximately 35 nM), potencies which were retained on mutant variants of the protease.
|
Antiviral activity against wild-type Hepatitis C virus genotype 1b N infected in human Huh7 cells
|
Hepatitis C virus subtype 1b
|
0.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Relative replication capacity and selective advantage profiles of protease inhibitor-resistant hepatitis C virus (HCV) NS3 protease mutants in the HCV genotype 1b replicon system.
Year : 2008
Volume : 52
Issue : 3
First Page : 1101
Last Page : 1110
Authors : He Y, King MS, Kempf DJ, Lu L, Lim HB, Krishnan P, Kati W, Middleton T, Molla A.
Abstract : We characterized the selective advantage profiles of a panel of hepatitis C virus (HCV) NS3 protease mutants with three HCV protease inhibitors (PIs), BILN-2061, ITMN-191, and VX-950, using a genotype 1b HCV replicon system. Selective advantage curves were generated by a novel mathematical method that factors in the degree of drug susceptibility provided by the mutation, the base-level replication capacity of the mutant in the absence of drugs, and the overall viral replication levels as a function of drug concentration. Most of the mutants showed significantly increased selective advantages over the wild-type species upon drug treatment. Each drug is associated with unique selective advantage profiles that reflect its antiviral activity and mutant susceptibility. Five mutants (R155K/Q, A156T, and D168A/V) showed significant levels of selective advantage after treatment with >10 nM ( approximately 7 times the wild-type 50% effective concentration [EC50]) of BILN-2061. R155K displayed dominant levels of selective advantage over the other mutants upon treatment with ITMN-191 over a broad range of concentrations. Upon VX-950 treatment, various mutants (A156T, A156S, R155K, T54A, V170A, V36M/R155K, and R155Q) exhibited high levels of selective advantage in different drug concentration ranges, with A156T and A156S being the dominant mutants at >3 microM ( approximately 10 times the wild-type EC50) of VX-950. This method provides more accurate estimates of the behavior of various mutants under drug pressure than replication capacity analysis. We noted that the R155K mutant shows reduced susceptibility to all three PIs and significant selective advantage, raising concern over the potential emergence of R155K as a multidrug-resistant, highly fit mutant in HCV patients treated with PIs.
|
Inhibition of HCV genotype 1 a NS3/4A protease by FRET assay
|
Hepatitis C virus subtype 1a
|
0.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of new acylsulfamoyl benzoxaboroles as potent inhibitors of HCV NS3 protease.
Year : 2010
Volume : 20
Issue : 24
First Page : 7493
Last Page : 7497
Authors : Li X, Zhang YK, Liu Y, Zhang S, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Liu L, Bu W, Kazmierski WM, Wright LL, Smith GK, Jarvest RL, Duan M, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Ni ZJ, Zou W, Wright J.
Abstract : HCV NS3/4A serine protease is essential for the replication of the HCV virus and has been a clinically validated target. A series of HCV NS3/4A protease inhibitors containing a novel acylsulfamoyl benzoxaborole moiety at the P1' region was synthesized and evaluated. The resulting P1-P3 and P2-P4 macrocyclic inhibitors exhibited sub-nanomolar potency in the enzymatic assay and low nanomolar activity in the cell-based replicon assay. The in vivo PK evaluations of selected compounds are also described.
|
Antiviral activity against HCV genotype 1a transfected in human hepatoma cell assessed as inhibition of viral replication
|
Hepatitis C virus subtype 1a
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of new acylsulfamoyl benzoxaboroles as potent inhibitors of HCV NS3 protease.
Year : 2010
Volume : 20
Issue : 24
First Page : 7493
Last Page : 7497
Authors : Li X, Zhang YK, Liu Y, Zhang S, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Liu L, Bu W, Kazmierski WM, Wright LL, Smith GK, Jarvest RL, Duan M, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Ni ZJ, Zou W, Wright J.
Abstract : HCV NS3/4A serine protease is essential for the replication of the HCV virus and has been a clinically validated target. A series of HCV NS3/4A protease inhibitors containing a novel acylsulfamoyl benzoxaborole moiety at the P1' region was synthesized and evaluated. The resulting P1-P3 and P2-P4 macrocyclic inhibitors exhibited sub-nanomolar potency in the enzymatic assay and low nanomolar activity in the cell-based replicon assay. The in vivo PK evaluations of selected compounds are also described.
|
Antiviral activity against HCV genotype 1b transfected in human hepatoma cell assessed as inhibition of viral replication
|
Hepatitis C virus subtype 1b
|
1.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of new acylsulfamoyl benzoxaboroles as potent inhibitors of HCV NS3 protease.
Year : 2010
Volume : 20
Issue : 24
First Page : 7493
Last Page : 7497
Authors : Li X, Zhang YK, Liu Y, Zhang S, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Liu L, Bu W, Kazmierski WM, Wright LL, Smith GK, Jarvest RL, Duan M, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Ni ZJ, Zou W, Wright J.
Abstract : HCV NS3/4A serine protease is essential for the replication of the HCV virus and has been a clinically validated target. A series of HCV NS3/4A protease inhibitors containing a novel acylsulfamoyl benzoxaborole moiety at the P1' region was synthesized and evaluated. The resulting P1-P3 and P2-P4 macrocyclic inhibitors exhibited sub-nanomolar potency in the enzymatic assay and low nanomolar activity in the cell-based replicon assay. The in vivo PK evaluations of selected compounds are also described.
|
Antiviral activity against HCV 1b infected in human Huh-7 cells after 48hrs by luciferase assay
|
Hepatitis C virus subtype 1b
|
1.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluations of P4-benzoxaborole-substituted macrocyclic inhibitors of HCV NS3 protease.
Year : 2010
Volume : 20
Issue : 24
First Page : 7317
Last Page : 7322
Authors : Ding CZ, Zhang YK, Li X, Liu Y, Zhang S, Zhou Y, Plattner JJ, Baker SJ, Liu L, Duan M, Jarvest RL, Ji J, Kazmierski WM, Tallant MD, Wright LL, Smith GK, Crosby RM, Wang AA, Ni ZJ, Zou W, Wright J.
Abstract : We disclose here a series of P4-benzoxaborole-substituted macrocyclic HCV protease inhibitors. These inhibitors are potent against HCV NS3 protease, their anti-HCV replicon potencies are largely impacted by substitutions on benzoxaborole ring system and P2∗ groups. P2∗ 2-thiazole-isoquinoline provides best replicon potency. The in vitro SAR studies and in vivo PK evaluations of selected compounds are described herein.
|
Antiviral activity against HCV 1a infected in human Huh-7 cells after 48hrs by luciferase assay
|
Hepatitis C virus subtype 1a
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluations of P4-benzoxaborole-substituted macrocyclic inhibitors of HCV NS3 protease.
Year : 2010
Volume : 20
Issue : 24
First Page : 7317
Last Page : 7322
Authors : Ding CZ, Zhang YK, Li X, Liu Y, Zhang S, Zhou Y, Plattner JJ, Baker SJ, Liu L, Duan M, Jarvest RL, Ji J, Kazmierski WM, Tallant MD, Wright LL, Smith GK, Crosby RM, Wang AA, Ni ZJ, Zou W, Wright J.
Abstract : We disclose here a series of P4-benzoxaborole-substituted macrocyclic HCV protease inhibitors. These inhibitors are potent against HCV NS3 protease, their anti-HCV replicon potencies are largely impacted by substitutions on benzoxaborole ring system and P2∗ groups. P2∗ 2-thiazole-isoquinoline provides best replicon potency. The in vitro SAR studies and in vivo PK evaluations of selected compounds are described herein.
|
Inhibition of HCV 1a NS3/4A protease by FRET assay
|
Hepatitis C virus subtype 1a
|
0.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluations of P4-benzoxaborole-substituted macrocyclic inhibitors of HCV NS3 protease.
Year : 2010
Volume : 20
Issue : 24
First Page : 7317
Last Page : 7322
Authors : Ding CZ, Zhang YK, Li X, Liu Y, Zhang S, Zhou Y, Plattner JJ, Baker SJ, Liu L, Duan M, Jarvest RL, Ji J, Kazmierski WM, Tallant MD, Wright LL, Smith GK, Crosby RM, Wang AA, Ni ZJ, Zou W, Wright J.
Abstract : We disclose here a series of P4-benzoxaborole-substituted macrocyclic HCV protease inhibitors. These inhibitors are potent against HCV NS3 protease, their anti-HCV replicon potencies are largely impacted by substitutions on benzoxaborole ring system and P2∗ groups. P2∗ 2-thiazole-isoquinoline provides best replicon potency. The in vitro SAR studies and in vivo PK evaluations of selected compounds are described herein.
|
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
|
0.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors.
Year : 2010
Volume : 54
Issue : 12
First Page : 5288
Last Page : 5297
Authors : Bae A, Sun SC, Qi X, Chen X, Ku K, Worth A, Wong KA, Harris J, Miller MD, Mo H.
Abstract : In order to assess the natural variation in susceptibility to hepatitis C virus (HCV) NS3 protease inhibitors (PIs) among untreated HCV patient samples, the susceptibilities of 39 baseline clinical isolates were determined using a transient-replication assay on a panel of HCV PIs, including two α-ketoamides (VX-950 and SCH-503034) and three macrocyclic inhibitors (MK-7009, ITMN-191, and TMC-435350). Some natural variation in susceptibility to all HCV PIs tested was observed among the baseline clinical isolates. The susceptibility to VX-950 correlated strongly with the susceptibility to SCH-503034. A moderate correlation was observed between the susceptibilities to ITMN-191 and MK-7009. In contrast, the phenotypic correlations between the α-ketoamides and macrocyclic inhibitors were significantly lower. This difference is partly attributable to reduced susceptibility of the HCV variants containing the NS3 polymorphism Q80K (existing in 47% of genotype 1a isolates) to the macrocyclic compounds but no change in the sensitivity of the same variants to the α-ketoamides tested. Our results suggest that the natural variation in baseline susceptibility may contribute to different degrees of antiviral response among patients in vivo, particularly at lower doses.
|
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
|
0.25
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors.
Year : 2010
Volume : 54
Issue : 12
First Page : 5288
Last Page : 5297
Authors : Bae A, Sun SC, Qi X, Chen X, Ku K, Worth A, Wong KA, Harris J, Miller MD, Mo H.
Abstract : In order to assess the natural variation in susceptibility to hepatitis C virus (HCV) NS3 protease inhibitors (PIs) among untreated HCV patient samples, the susceptibilities of 39 baseline clinical isolates were determined using a transient-replication assay on a panel of HCV PIs, including two α-ketoamides (VX-950 and SCH-503034) and three macrocyclic inhibitors (MK-7009, ITMN-191, and TMC-435350). Some natural variation in susceptibility to all HCV PIs tested was observed among the baseline clinical isolates. The susceptibility to VX-950 correlated strongly with the susceptibility to SCH-503034. A moderate correlation was observed between the susceptibilities to ITMN-191 and MK-7009. In contrast, the phenotypic correlations between the α-ketoamides and macrocyclic inhibitors were significantly lower. This difference is partly attributable to reduced susceptibility of the HCV variants containing the NS3 polymorphism Q80K (existing in 47% of genotype 1a isolates) to the macrocyclic compounds but no change in the sensitivity of the same variants to the α-ketoamides tested. Our results suggest that the natural variation in baseline susceptibility may contribute to different degrees of antiviral response among patients in vivo, particularly at lower doses.
|
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
|
0.62
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors.
Year : 2010
Volume : 54
Issue : 12
First Page : 5288
Last Page : 5297
Authors : Bae A, Sun SC, Qi X, Chen X, Ku K, Worth A, Wong KA, Harris J, Miller MD, Mo H.
Abstract : In order to assess the natural variation in susceptibility to hepatitis C virus (HCV) NS3 protease inhibitors (PIs) among untreated HCV patient samples, the susceptibilities of 39 baseline clinical isolates were determined using a transient-replication assay on a panel of HCV PIs, including two α-ketoamides (VX-950 and SCH-503034) and three macrocyclic inhibitors (MK-7009, ITMN-191, and TMC-435350). Some natural variation in susceptibility to all HCV PIs tested was observed among the baseline clinical isolates. The susceptibility to VX-950 correlated strongly with the susceptibility to SCH-503034. A moderate correlation was observed between the susceptibilities to ITMN-191 and MK-7009. In contrast, the phenotypic correlations between the α-ketoamides and macrocyclic inhibitors were significantly lower. This difference is partly attributable to reduced susceptibility of the HCV variants containing the NS3 polymorphism Q80K (existing in 47% of genotype 1a isolates) to the macrocyclic compounds but no change in the sensitivity of the same variants to the α-ketoamides tested. Our results suggest that the natural variation in baseline susceptibility may contribute to different degrees of antiviral response among patients in vivo, particularly at lower doses.
|
Antiviral activity against HCV
|
Hepatitis C virus
|
0.6
nM
|
|
Journal : Bioorg. Med. Chem.
Title : P2-P1' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis.
Year : 2011
Volume : 19
Issue : 16
First Page : 4917
Last Page : 4927
Authors : Lampa A, Ehrenberg AE, Vema A, Åkerblom E, Lindeberg G, Danielson UH, Karlén A, Sandström A.
Abstract : Macrocyclization is a commonly used strategy to preorganize HCV NS3 protease inhibitors in their bioactive conformation. Moreover, macrocyclization generally leads to greater stability and improved pharmacokinetic properties. In HCV NS3 protease inhibitors, it has been shown to be beneficial to include a vinylated phenylglycine in the P2 position in combination with alkenylic P1' substituents. A series of 14-, 15- and 16-membered macrocyclic HCV NS3 protease inhibitors with the linker connecting the P2 phenylglycine and the alkenylic P1' were synthesized by ring-closing metathesis, using both microwave and conventional heating. Besides formation of the expected macrocycles in cis and trans configuration as major products, both ring-contracted and double-bond migrated isomers were obtained, in particular during formation of the smaller rings (14- and 15-membered rings). All inhibitors had K(i)-values in the nanomolar range, but only one inhibitor type was improved by rigidification. The loss in inhibitory effect can be attributed to a disruption of the beneficial π-π interaction between the P2 fragment and H57, which proved to be especially deleterious for the d-phenylglycine epimers.
|
Inhibition of HCV NS3 protease
|
Hepatitis C virus
|
0.25
nM
|
|
Journal : Bioorg. Med. Chem.
Title : P2-P1' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis.
Year : 2011
Volume : 19
Issue : 16
First Page : 4917
Last Page : 4927
Authors : Lampa A, Ehrenberg AE, Vema A, Åkerblom E, Lindeberg G, Danielson UH, Karlén A, Sandström A.
Abstract : Macrocyclization is a commonly used strategy to preorganize HCV NS3 protease inhibitors in their bioactive conformation. Moreover, macrocyclization generally leads to greater stability and improved pharmacokinetic properties. In HCV NS3 protease inhibitors, it has been shown to be beneficial to include a vinylated phenylglycine in the P2 position in combination with alkenylic P1' substituents. A series of 14-, 15- and 16-membered macrocyclic HCV NS3 protease inhibitors with the linker connecting the P2 phenylglycine and the alkenylic P1' were synthesized by ring-closing metathesis, using both microwave and conventional heating. Besides formation of the expected macrocycles in cis and trans configuration as major products, both ring-contracted and double-bond migrated isomers were obtained, in particular during formation of the smaller rings (14- and 15-membered rings). All inhibitors had K(i)-values in the nanomolar range, but only one inhibitor type was improved by rigidification. The loss in inhibitory effect can be attributed to a disruption of the beneficial π-π interaction between the P2 fragment and H57, which proved to be especially deleterious for the d-phenylglycine epimers.
|
Inhibition of Hepatitis C virus genotype 1a NS3/4A protease using Ac-DE-Dap(QXL520)-EE-Abu-psi-COO]-AS-C(5-FAMsp)-NH2 as substrate by FRET analysis
|
Hepatitis C virus subtype 1a
|
0.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel P3-oxo inhibitor of hepatitis C virus NS3/4A serine protease.
Year : 2012
Volume : 22
Issue : 8
First Page : 2993
Last Page : 2996
Authors : Duan M, Kazmierski W, Crosby R, Gartland M, Ji J, Tallant M, Wang A, Hamatake R, Wright L, Wu M, Zhang YK, Ding CZ, Li X, Liu Y, Zhang S, Zhou Y, Plattner JJ, Baker SJ.
Abstract : A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.
|
Antiviral activity against Hepatitis C virus genotype 1b infected in HuH7 cells
|
Hepatitis C virus subtype 1b
|
1.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel P3-oxo inhibitor of hepatitis C virus NS3/4A serine protease.
Year : 2012
Volume : 22
Issue : 8
First Page : 2993
Last Page : 2996
Authors : Duan M, Kazmierski W, Crosby R, Gartland M, Ji J, Tallant M, Wang A, Hamatake R, Wright L, Wu M, Zhang YK, Ding CZ, Li X, Liu Y, Zhang S, Zhou Y, Plattner JJ, Baker SJ.
Abstract : A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.
|
Antiviral activity against Hepatitis C virus genotype 1a infected in HuH7 cells
|
Hepatitis C virus subtype 1a
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel P3-oxo inhibitor of hepatitis C virus NS3/4A serine protease.
Year : 2012
Volume : 22
Issue : 8
First Page : 2993
Last Page : 2996
Authors : Duan M, Kazmierski W, Crosby R, Gartland M, Ji J, Tallant M, Wang A, Hamatake R, Wright L, Wu M, Zhang YK, Ding CZ, Li X, Liu Y, Zhang S, Zhou Y, Plattner JJ, Baker SJ.
Abstract : A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.
|
Antiviral activity against Hepatitis C virus genotype 1b expressing wild type NS3/4A protease infected in HuH7 cells
|
Hepatitis C virus subtype 1b
|
0.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel P3-oxo inhibitor of hepatitis C virus NS3/4A serine protease.
Year : 2012
Volume : 22
Issue : 8
First Page : 2993
Last Page : 2996
Authors : Duan M, Kazmierski W, Crosby R, Gartland M, Ji J, Tallant M, Wang A, Hamatake R, Wright L, Wu M, Zhang YK, Ding CZ, Li X, Liu Y, Zhang S, Zhou Y, Plattner JJ, Baker SJ.
Abstract : A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.
|
Antiviral activity against Hepatitis C virus genotype 1b expressing NS3/4A protease A156S mutant infected in HuH7 cells
|
Hepatitis C virus subtype 1b
|
1.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel P3-oxo inhibitor of hepatitis C virus NS3/4A serine protease.
Year : 2012
Volume : 22
Issue : 8
First Page : 2993
Last Page : 2996
Authors : Duan M, Kazmierski W, Crosby R, Gartland M, Ji J, Tallant M, Wang A, Hamatake R, Wright L, Wu M, Zhang YK, Ding CZ, Li X, Liu Y, Zhang S, Zhou Y, Plattner JJ, Baker SJ.
Abstract : A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.
|
Antiviral activity against Hepatitis C virus genotype 1b expressing NS3/4A protease A156T mutant infected in HuH7 cells
|
Hepatitis C virus subtype 1b
|
6.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel P3-oxo inhibitor of hepatitis C virus NS3/4A serine protease.
Year : 2012
Volume : 22
Issue : 8
First Page : 2993
Last Page : 2996
Authors : Duan M, Kazmierski W, Crosby R, Gartland M, Ji J, Tallant M, Wang A, Hamatake R, Wright L, Wu M, Zhang YK, Ding CZ, Li X, Liu Y, Zhang S, Zhou Y, Plattner JJ, Baker SJ.
Abstract : A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.
|
Antiviral activity against Hepatitis C virus genotype 1b expressing NS3/4A protease A156V mutant infected in HuH7 cells
|
Hepatitis C virus subtype 1b
|
8.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel P3-oxo inhibitor of hepatitis C virus NS3/4A serine protease.
Year : 2012
Volume : 22
Issue : 8
First Page : 2993
Last Page : 2996
Authors : Duan M, Kazmierski W, Crosby R, Gartland M, Ji J, Tallant M, Wang A, Hamatake R, Wright L, Wu M, Zhang YK, Ding CZ, Li X, Liu Y, Zhang S, Zhou Y, Plattner JJ, Baker SJ.
Abstract : A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.
|
Antiviral activity against Hepatitis C virus genotype 1b expressing NS3/4A protease D158A mutant infected in HuH7 cells
|
Hepatitis C virus subtype 1b
|
48.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel P3-oxo inhibitor of hepatitis C virus NS3/4A serine protease.
Year : 2012
Volume : 22
Issue : 8
First Page : 2993
Last Page : 2996
Authors : Duan M, Kazmierski W, Crosby R, Gartland M, Ji J, Tallant M, Wang A, Hamatake R, Wright L, Wu M, Zhang YK, Ding CZ, Li X, Liu Y, Zhang S, Zhou Y, Plattner JJ, Baker SJ.
Abstract : A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.
|
Antiviral activity against Hepatitis C virus genotype 1b expressing NS3/4A protease D158V mutant infected in HuH7 cells
|
Hepatitis C virus subtype 1b
|
24.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel P3-oxo inhibitor of hepatitis C virus NS3/4A serine protease.
Year : 2012
Volume : 22
Issue : 8
First Page : 2993
Last Page : 2996
Authors : Duan M, Kazmierski W, Crosby R, Gartland M, Ji J, Tallant M, Wang A, Hamatake R, Wright L, Wu M, Zhang YK, Ding CZ, Li X, Liu Y, Zhang S, Zhou Y, Plattner JJ, Baker SJ.
Abstract : A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.
|
Antiviral activity against Hepatitis C virus genotype 1b expressing NS3/4A protease R155K mutant infected in HuH7 cells
|
Hepatitis C virus subtype 1b
|
80.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel P3-oxo inhibitor of hepatitis C virus NS3/4A serine protease.
Year : 2012
Volume : 22
Issue : 8
First Page : 2993
Last Page : 2996
Authors : Duan M, Kazmierski W, Crosby R, Gartland M, Ji J, Tallant M, Wang A, Hamatake R, Wright L, Wu M, Zhang YK, Ding CZ, Li X, Liu Y, Zhang S, Zhou Y, Plattner JJ, Baker SJ.
Abstract : A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.
|
Inhibition of HCV 1a protease 1a domain
|
Hepatitis C virus
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b by stable replicon assay
|
Hepatitis C virus subtype 1b
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1a by stable replicon assay
|
Hepatitis C virus subtype 1a
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b harboring protease D168V mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
26.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b harboring protease D168A mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
39.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b harboring protease A156V mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b harboring protease A156T mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b harboring protease A156S mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against wild type Hepatitis C virus subtype 1b by transient replicon assay
|
Hepatitis C virus subtype 1b
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b harboring protease R155K mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
82.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Inhibition of HCV6 NS3 protease
|
Hepatitis C virus genotype 6
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.
Year : 2011
Volume : 54
Issue : 7
First Page : 1961
Last Page : 2004
Authors : Marsault E, Peterson ML.
|
Inhibition of HCV4 NS3 protease
|
Hepatitis C virus genotype 4
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.
Year : 2011
Volume : 54
Issue : 7
First Page : 1961
Last Page : 2004
Authors : Marsault E, Peterson ML.
|
Inhibition of HCV5 NS3 protease
|
Hepatitis C virus genotype 5
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.
Year : 2011
Volume : 54
Issue : 7
First Page : 1961
Last Page : 2004
Authors : Marsault E, Peterson ML.
|
Inhibition of HCV 2b NS3 protease
|
Hepatitis C virus subtype 2b
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.
Year : 2011
Volume : 54
Issue : 7
First Page : 1961
Last Page : 2004
Authors : Marsault E, Peterson ML.
|
Inhibition of HCV 3a NS3 protease
|
Hepatitis C virus subtype 3a
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.
Year : 2011
Volume : 54
Issue : 7
First Page : 1961
Last Page : 2004
Authors : Marsault E, Peterson ML.
|
Antiviral activity against HCV by cell based replicon assay
|
Hepatitis C virus
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.
Year : 2011
Volume : 54
Issue : 7
First Page : 1961
Last Page : 2004
Authors : Marsault E, Peterson ML.
|
Inhibition of HCV 1a NS3 protease
|
Hepatitis C virus subtype 1a
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.
Year : 2011
Volume : 54
Issue : 7
First Page : 1961
Last Page : 2004
Authors : Marsault E, Peterson ML.
|
Inhibition of HCV 1b NS3 protease
|
Hepatitis C virus subtype 1b
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.
Year : 2011
Volume : 54
Issue : 7
First Page : 1961
Last Page : 2004
Authors : Marsault E, Peterson ML.
|
Antiviral activity against HCV subtype 1b expressing NS3/4A R115K mutant protease infected in ET cells after 72 hrs
|
Hepatitis C virus subtype 1b
|
82.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups.
Year : 2012
Volume : 22
Issue : 24
First Page : 7351
Last Page : 7356
Authors : Li X, Liu Y, Zhang YK, Plattner JJ, Baker SJ, Bu W, Liu L, Zhou Y, Ding CZ, Zhang S, Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A.
Abstract : We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
|
Antiviral activity against HCV subtype 1b expressing NS3/4A D168V mutant protease infected in ET cells after 72 hrs
|
Hepatitis C virus subtype 1b
|
26.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups.
Year : 2012
Volume : 22
Issue : 24
First Page : 7351
Last Page : 7356
Authors : Li X, Liu Y, Zhang YK, Plattner JJ, Baker SJ, Bu W, Liu L, Zhou Y, Ding CZ, Zhang S, Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A.
Abstract : We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
|
Antiviral activity against HCV subtype 1b expressing NS3/4A D168A mutant protease infected in ET cells after 72 hrs
|
Hepatitis C virus subtype 1b
|
39.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups.
Year : 2012
Volume : 22
Issue : 24
First Page : 7351
Last Page : 7356
Authors : Li X, Liu Y, Zhang YK, Plattner JJ, Baker SJ, Bu W, Liu L, Zhou Y, Ding CZ, Zhang S, Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A.
Abstract : We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
|
Antiviral activity against HCV subtype 1b expressing NS3/4A A156V mutant protease infected in ET cells after 72 hrs
|
Hepatitis C virus subtype 1b
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups.
Year : 2012
Volume : 22
Issue : 24
First Page : 7351
Last Page : 7356
Authors : Li X, Liu Y, Zhang YK, Plattner JJ, Baker SJ, Bu W, Liu L, Zhou Y, Ding CZ, Zhang S, Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A.
Abstract : We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
|
Antiviral activity against HCV subtype 1b expressing NS3/4A A156T mutant protease infected in ET cells after 72 hrs
|
Hepatitis C virus subtype 1b
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups.
Year : 2012
Volume : 22
Issue : 24
First Page : 7351
Last Page : 7356
Authors : Li X, Liu Y, Zhang YK, Plattner JJ, Baker SJ, Bu W, Liu L, Zhou Y, Ding CZ, Zhang S, Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A.
Abstract : We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
|
Antiviral activity against HCV subtype 1b expressing NS3/4A A156S mutant protease infected in ET cells after 72 hrs
|
Hepatitis C virus subtype 1b
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups.
Year : 2012
Volume : 22
Issue : 24
First Page : 7351
Last Page : 7356
Authors : Li X, Liu Y, Zhang YK, Plattner JJ, Baker SJ, Bu W, Liu L, Zhou Y, Ding CZ, Zhang S, Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A.
Abstract : We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
|
Antiviral activity against HCV subtype 1b expressing wild type NS3/4A protease infected in ET cells after 72 hrs
|
Hepatitis C virus subtype 1b
|
0.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups.
Year : 2012
Volume : 22
Issue : 24
First Page : 7351
Last Page : 7356
Authors : Li X, Liu Y, Zhang YK, Plattner JJ, Baker SJ, Bu W, Liu L, Zhou Y, Ding CZ, Zhang S, Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A.
Abstract : We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
|
Antiviral activity against HCV subtype 1b infected in human hepatoma cells
|
Hepatitis C virus subtype 1b
|
1.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups.
Year : 2012
Volume : 22
Issue : 24
First Page : 7351
Last Page : 7356
Authors : Li X, Liu Y, Zhang YK, Plattner JJ, Baker SJ, Bu W, Liu L, Zhou Y, Ding CZ, Zhang S, Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A.
Abstract : We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
|
Antiviral activity against HCV subtype 1a infected in human hepatoma cells
|
Hepatitis C virus subtype 1a
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups.
Year : 2012
Volume : 22
Issue : 24
First Page : 7351
Last Page : 7356
Authors : Li X, Liu Y, Zhang YK, Plattner JJ, Baker SJ, Bu W, Liu L, Zhou Y, Ding CZ, Zhang S, Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A.
Abstract : We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
|
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
|
0.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups.
Year : 2012
Volume : 22
Issue : 24
First Page : 7351
Last Page : 7356
Authors : Li X, Liu Y, Zhang YK, Plattner JJ, Baker SJ, Bu W, Liu L, Zhou Y, Ding CZ, Zhang S, Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A.
Abstract : We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
|
Antiviral activity against Hepatitis C virus harboring NS3/4A protease A156T mutant gene infected in human HuH7 cells assessed as inhibition of HCV subgenomic replicon replication after 72 hrs by ELISA
|
Hepatitis C virus
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Antiviral activity against Hepatitis C virus harboring wild type NS3/4A protease infected in human HuH7 cells assessed as inhibition of HCV subgenomic replicon replication after 72 hrs by ELISA
|
Hepatitis C virus
|
0.25
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Antiviral activity against Hepatitis C virus genotype 1a isolate Con1 harboring NS3/4A protease A156T mutant gene infected in human HuH7 cells assessed as inhibition of HCV replicon replication by luciferase assay
|
Hepatitis C virus (isolate Con1)
|
5.7
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Antiviral activity against Hepatitis C virus genotype 1a isolate Con1 harboring wild type NS3/4A protease infected in human HuH7 cells assessed as inhibition of HCV replicon replication by luciferase assay
|
Hepatitis C virus (isolate Con1)
|
0.24
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Inhibition of Hepatitis C virus genotype 1a NS3/4A protease A156T mutant expressed in Escherichia coli BL21 (DE3) cells assessed as substrate cleavage using Ac-DE-Dap(QXL520)-EE-Abu-psi-[COO]AS-C(5-FAMsp)-NH2 as substrate by plate reader analysis
|
Hepatitis C virus subtype 1a
|
44.8
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Inhibition of Hepatitis C virus genotype 1a wild type NS3/4A protease expressed in Escherichia coli BL21 (DE3) cells assessed as substrate cleavage using Ac-DE-Dap(QXL520)-EE-Abu-psi-[COO]AS-C(5-FAMsp)-NH2 as substrate by plate reader analysis
|
Hepatitis C virus subtype 1a
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Antiviral activity against Hepatitis C virus genotype 3 infected in human HuH7 cells assessed as decrease in replicon RNA level after 2 days by TaqMan Gold RT-PCR analysis
|
Hepatitis C virus genotype 3
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Antiviral activity against Hepatitis C virus genotype 1b infected in human HuH7 cells assessed as decrease in replicon RNA level after 2 days by TaqMan Gold RT-PCR analysis
|
Hepatitis C virus subtype 1b
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Antiviral activity against Hepatitis C virus genotype 2 infected in human HuH7 cells assessed as decrease in replicon RNA level after 2 days by TaqMan Gold RT-PCR analysis
|
Hepatitis C virus genotype 2
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Inhibition of Hepatitis C virus genotype 3a NS3/4A protease using Ac-DE-Dap(QXL520)-EE-Abu-psi-[COO]-AS-Cys(5-FAMsp)-NH2 as substrate by FRET analysis
|
Hepatitis C virus subtype 3a
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Inhibition of Hepatitis C virus genotype 2b NS3/4A protease using Ac-DE-Dap(QXL520)-EE-Abu-psi-[COO]-AS-Cys(5-FAMsp)-NH2 as substrate by FRET analysis
|
Hepatitis C virus subtype 2b
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Inhibition of Hepatitis C virus genotype 6 NS3/4A protease using Ac-DE-Dap(QXL520)-EE-Abu-psi-[COO]-AS-Cys(5-FAMsp)-NH2 as substrate by FRET analysis
|
Hepatitis C virus genotype 6
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Inhibition of Hepatitis C virus genotype 5 NS3/4A protease using Ac-DE-Dap(QXL520)-EE-Abu-psi-[COO]-AS-Cys(5-FAMsp)-NH2 as substrate by FRET analysis
|
Hepatitis C virus genotype 5
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Inhibition of Hepatitis C virus genotype 4 NS3/4A protease using Ac-DE-Dap(QXL520)-EE-Abu-psi-[COO]-AS-Cys(5-FAMsp)-NH2 as substrate by FRET analysis
|
Hepatitis C virus genotype 4
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease using Ac-DE-Dap(QXL520)-EE-Abu-psi-[COO]-AS-Cys(5-FAMsp)-NH2 as substrate by FRET analysis
|
Hepatitis C virus subtype 1b
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Inhibition of Hepatitis C virus genotype 1a NS3/4A protease using Ac-DE-Dap(QXL520)-EE-Abu-psi-[COO]-AS-Cys(5-FAMsp)-NH2 as substrate by FRET analysis
|
Hepatitis C virus subtype 1a
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Antiviral activity against Hepatitis C virus infected in human HuH7 cells assessed as inhibition of HCV subgenomic replicon replication after 72 hrs by ELISA
|
Hepatitis C virus
|
2.4
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Inhibition of Hepatitis C virus full-length NS3/4A protease assessed as quenched-fluorogenic RET-S1 substrate cleavage incubated for 10 mins prior to substrate addition by FRET analysis
|
Hepatitis C virus
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.
Year : 2014
Volume : 57
Issue : 5
First Page : 1753
Last Page : 1769
Authors : Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, Kennedy AL, Madduru MR, Wang B, Lyon M, Doherty GA, Woodard BT, Lemieux C, Geck Do M, Zhang H, Ballard J, Vigers G, Brandhuber BJ, Stengel P, Josey JA, Beigelman L, Blatt L, Seiwert SD.
Abstract : HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
|
Inhibition of Hepatitis C virus genotype 3a full-length NS3 protease assessed as overall/observed affinity by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 3a
|
0.52
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1b full-length NS3/NS4A protease assessed as overall/observed affinity by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1b
|
6.5
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1b full-length NS3 protease assessed as overall/observed affinity by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1b
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1a full-length NS3/NS4A protease assessed as overall/observed affinity by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1a
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1a full-length NS3 protease assessed as overall/observed affinity by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1a
|
0.13
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 3a full-length NS3 protease assessed as equilibrium dissociation constant by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 3a
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1b full-length NS3/NS4A protease assessed as equilibrium dissociation constant by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1b
|
6.5
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1b full-length NS3 protease assessed as equilibrium dissociation constant by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1b
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1a full-length NS3/NS4A protease assessed as equilibrium dissociation constant by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1a
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1a full-length NS3 protease assessed as equilibrium dissociation constant by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1a
|
2.5
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of full-length HCV genotype 1a NS3 protease R155K mutant using Ac-DED(Edans)EEAbu-psi-[COO]ASK(Dabcyl)-NH2 as substrate by FRET assay
|
Hepatitis C virus subtype 1a
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of pyrazinone based compounds that potently inhibit the drug-resistant enzyme variant R155K of the hepatitis C virus NS3 protease.
Year : 2016
Volume : 24
Issue : 12
First Page : 2603
Last Page : 2620
Authors : Belfrage AK, Abdurakhmanov E, Kerblom E, Brandt P, Oshalim A, Gising J, Skogh A, Neyts J, Danielson UH, Sandström A.
Abstract : Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wild-type and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.
|
Antiviral activity against HCV infected in human HuH7 cells by cell based replicon assay
|
Hepatitis C virus
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of pyrazinone based compounds that potently inhibit the drug-resistant enzyme variant R155K of the hepatitis C virus NS3 protease.
Year : 2016
Volume : 24
Issue : 12
First Page : 2603
Last Page : 2620
Authors : Belfrage AK, Abdurakhmanov E, Kerblom E, Brandt P, Oshalim A, Gising J, Skogh A, Neyts J, Danielson UH, Sandström A.
Abstract : Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wild-type and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.
|
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
|
3.46
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
20.22
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
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
|
-0.06
%
|
|
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
|
-0.06
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of HCV NS3/4a protease using Ac-DE-Dap(QXL520)-EE-Abu-shi-[COO]AS-C(5-FAMsp)-NH2 as substrate after 15 mins
|
Hepatitis C virus
|
0.2
nM
|
|
Journal : Eur J Med Chem
Title : A review on HCV inhibitors: Significance of non-structural polyproteins.
Year : 2019
Volume : 164
First Page : 576
Last Page : 601
Authors : Ganta NM, Gedda G, Rathnakar B, Satyanarayana M, Yamajala B, Ahsan MJ, Jadav SS, Balaraju T.
Abstract : Hepatitis C virus (HCV) mortality and morbidity is a world health misery with an approximate 130-150 million chronically HCV tainted and suffering individuals and it initiate critical liver malfunction like cirrhosis, hepatocellular carcinoma or liver HCV cancer. HCV NS5B protein one of the best studied therapeutic target for the identification of new drug candidates to be added to the combination or multiple combination medication recently approved. During the past few years, NS5B has thus been an important object of attractive medicinal chemistry endeavors, which induced to the surfacing of betrothal preclinical drug molecules. In this scenario, the current review set limit to discuss research published on NS5B and few other therapeutic functional inhibitors concentrating on hit investigation, hit to lead optimization, ADME parameters evaluation, and the SAR data which was out for each compound type and similarity taken into consideration. The discussion outlined in this specific review will surly helpful and vital tool for those medicinal chemists investigators working with HCV research programs mainly pointing on NS5B and set broad spectrum identification of creative anti HCV compounds. This mini review also tells each and every individual compound ability related how much they are active against NS5B and few other targets.
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Antiviral activity against HCV
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Hepatitis C virus
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17.5
nM
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Journal : Eur J Med Chem
Title : A review on HCV inhibitors: Significance of non-structural polyproteins.
Year : 2019
Volume : 164
First Page : 576
Last Page : 601
Authors : Ganta NM, Gedda G, Rathnakar B, Satyanarayana M, Yamajala B, Ahsan MJ, Jadav SS, Balaraju T.
Abstract : Hepatitis C virus (HCV) mortality and morbidity is a world health misery with an approximate 130-150 million chronically HCV tainted and suffering individuals and it initiate critical liver malfunction like cirrhosis, hepatocellular carcinoma or liver HCV cancer. HCV NS5B protein one of the best studied therapeutic target for the identification of new drug candidates to be added to the combination or multiple combination medication recently approved. During the past few years, NS5B has thus been an important object of attractive medicinal chemistry endeavors, which induced to the surfacing of betrothal preclinical drug molecules. In this scenario, the current review set limit to discuss research published on NS5B and few other therapeutic functional inhibitors concentrating on hit investigation, hit to lead optimization, ADME parameters evaluation, and the SAR data which was out for each compound type and similarity taken into consideration. The discussion outlined in this specific review will surly helpful and vital tool for those medicinal chemists investigators working with HCV research programs mainly pointing on NS5B and set broad spectrum identification of creative anti HCV compounds. This mini review also tells each and every individual compound ability related how much they are active against NS5B and few other targets.
