|
Antiviral activity against Hepatitis C virus genotype 1B by whole cell replicon assay
|
Hepatitis C virus subtype 1b
|
0.009
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics.
Year : 2012
Volume : 22
Issue : 8
First Page : 2938
Last Page : 2942
Authors : Chang W, Mosley RT, Bansal S, Keilman M, Lam AM, Furman PA, Otto MJ, Sofia MJ.
Abstract : The HCV non-structural protein NS5A has been established as a viable target for the development of direct acting antiviral therapy. From computational modeling studies strong intra-molecular hydrogen bonds were found to be a common structural moiety within known NS5A inhibitors that have low pico-molar replicon potency. Efforts to reproduce these γ-turn-like substructures provided a novel NS5A inhibitor based on a fluoro-olefin isostere. This fluoro-olefin containing inhibitor exhibited picomolar activity (EC(50)=79 pM) against HCV genotype 1b replicon without measurable cytotoxicity. This level of activity is comparable to the natural peptide-based inhibitors currently under clinic evaluation, and demonstrates that a peptidomimetic approach can serve as a useful strategy to produce potent and structurally unique inhibitors of HCV NS5A.
|
Antiviral activity against Hepatitis C virus genotype 1A by whole cell replicon assay
|
Hepatitis C virus subtype 1b
|
0.05
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics.
Year : 2012
Volume : 22
Issue : 8
First Page : 2938
Last Page : 2942
Authors : Chang W, Mosley RT, Bansal S, Keilman M, Lam AM, Furman PA, Otto MJ, Sofia MJ.
Abstract : The HCV non-structural protein NS5A has been established as a viable target for the development of direct acting antiviral therapy. From computational modeling studies strong intra-molecular hydrogen bonds were found to be a common structural moiety within known NS5A inhibitors that have low pico-molar replicon potency. Efforts to reproduce these γ-turn-like substructures provided a novel NS5A inhibitor based on a fluoro-olefin isostere. This fluoro-olefin containing inhibitor exhibited picomolar activity (EC(50)=79 pM) against HCV genotype 1b replicon without measurable cytotoxicity. This level of activity is comparable to the natural peptide-based inhibitors currently under clinic evaluation, and demonstrates that a peptidomimetic approach can serve as a useful strategy to produce potent and structurally unique inhibitors of HCV NS5A.
|
Antiviral activity against Hepatitis C virus genotype 2A by whole cell replicon assay
|
Hepatitis C virus subtype 2a
|
0.063
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics.
Year : 2012
Volume : 22
Issue : 8
First Page : 2938
Last Page : 2942
Authors : Chang W, Mosley RT, Bansal S, Keilman M, Lam AM, Furman PA, Otto MJ, Sofia MJ.
Abstract : The HCV non-structural protein NS5A has been established as a viable target for the development of direct acting antiviral therapy. From computational modeling studies strong intra-molecular hydrogen bonds were found to be a common structural moiety within known NS5A inhibitors that have low pico-molar replicon potency. Efforts to reproduce these γ-turn-like substructures provided a novel NS5A inhibitor based on a fluoro-olefin isostere. This fluoro-olefin containing inhibitor exhibited picomolar activity (EC(50)=79 pM) against HCV genotype 1b replicon without measurable cytotoxicity. This level of activity is comparable to the natural peptide-based inhibitors currently under clinic evaluation, and demonstrates that a peptidomimetic approach can serve as a useful strategy to produce potent and structurally unique inhibitors of HCV NS5A.
|
Antiviral activity against HCV1b infected in human HuH7 cells assessed as inhibition of viral replication by RT-PCR analysis
|
Hepatitis C virus subtype 1b
|
0.0066
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of new potent and selective HCV NS5A inhibitors.
Year : 2012
Volume : 22
Issue : 10
First Page : 3488
Last Page : 3491
Authors : Shi J, Zhou L, Amblard F, Bobeck DR, Zhang H, Liu P, Bondada L, McBrayer TR, Tharnish PM, Whitaker T, Coats SJ, Schinazi RF.
Abstract : NS5A inhibitors are a new class of direct-acting antiviral agents which display very potent anti-HCV activity in vitro and in humans. Rationally designed modifications to the central biphenyl linkage of a known NS5A series led to selection of several compounds that were synthesized and evaluated in a HCV genotype 1b replicon. The straight triphenyl linked compound 11a showed similar anti-HCV activity to the clinical compound BMS-790052 and a superior cytotoxicity profile in three different cell lines, with an EC(50) value of 26 pM and a therapeutic index of over four million in an HCV replicon assay. This triphenyl analog warrants further preclinical evaluation as an anti-HCV agent.
|
Inhibition of HCV NS5A assessed as antiviral activity against HCV by viral replicon assay
|
Hepatitis C virus
|
0.0042
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of novel potent HCV NS5A inhibitors.
Year : 2012
Volume : 22
Issue : 14
First Page : 4864
Last Page : 4868
Authors : Zhang H, Zhou L, Amblard F, Shi J, Bobeck DR, Tao S, McBrayer TR, Tharnish PM, Whitaker T, Coats SJ, Schinazi RF.
Abstract : Judicious modifications to the structure of the previously reported HCV NS5A inhibitor 1, resulted in more potent anti-HCV compounds with similar and in some cases improved toxicity profiles. The synthesis of 19 new NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. For the most potent compounds chemical stability, stability in liver microsomes and inhibition of relevant CYP450 enzymes is also presented.
|
Antiviral activity against HCV 1b infected in human HuH7 cells by in vitro replicon assay
|
Hepatitis C virus subtype 1b
|
0.01
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of non-dimeric HCV NS5A inhibitors.
Year : 2013
Volume : 23
Issue : 7
First Page : 2031
Last Page : 2034
Authors : Amblard F, Zhang H, Zhou L, Shi J, Bobeck DR, Nettles JH, Chavre S, McBrayer TR, Tharnish P, Whitaker T, Coats SJ, Schinazi RF.
Abstract : Based on the symmetrical bidentate structure of the NS5A inhibitor BMS-790052, a series of new monodentate molecules were designed. The synthesis of 36 new non-dimeric NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. Among them compound 5a showed picomolar range activity along with an excellent selectivity index (SI > 90,000).
|
Antiviral activity against Hepatitis C virus genotype 1b infected in human Huh-5.2 cells assessed as decrease in HCV replicon RNA replication after 4 days by luciferase assay
|
Hepatitis C virus subtype 1b
|
0.009
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of Thienoimidazole-Based HCV NS5A Genotype 1a and 1b Inhibitors.
Year : 2014
Volume : 5
Issue : 3
First Page : 240
Last Page : 243
Authors : Giroux S, Xu J, Reddy TJ, Morris M, Cottrell KM, Cadilhac C, Henderson JA, Nicolas O, Bilimoria D, Denis F, Mani N, Ewing N, Shawgo R, L'Heureux L, Selliah S, Chan L, Chauret N, Berlioz-Seux F, Namchuk MN, Grillot AL, Bennani YL, Das SK, Maxwell JP.
Abstract : The discovery of potent thienoimidazole-based HCV NS5A inhibitors is herein reported. A novel method to access the thienoimidazole [5,5]-bicyclic system is disclosed. This method gave access to a common key intermediate (6) that was engaged in Suzuki or Sonogashira reactions with coupling partners bearing different linkers. A detailed study of the structure-activity relationship (SAR) of the linkers revealed that aromatic linkers with linear topologies are required to achieve high potency for both 1a and 1b HCV genotypes. Compound 20, with a para-phenyl linker, was identified as a potential lead displaying potencies of 17 and 8 pM against genotype 1a and 1b replicons, respectively.
|
Antiviral activity against Hepatitis C virus genotype 1a infected in W11.8 cells assessed as decrease in NS5A expression in replicon cell after 4 days by luminescence based ELISA
|
Hepatitis C virus subtype 1a
|
0.05
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of Thienoimidazole-Based HCV NS5A Genotype 1a and 1b Inhibitors.
Year : 2014
Volume : 5
Issue : 3
First Page : 240
Last Page : 243
Authors : Giroux S, Xu J, Reddy TJ, Morris M, Cottrell KM, Cadilhac C, Henderson JA, Nicolas O, Bilimoria D, Denis F, Mani N, Ewing N, Shawgo R, L'Heureux L, Selliah S, Chan L, Chauret N, Berlioz-Seux F, Namchuk MN, Grillot AL, Bennani YL, Das SK, Maxwell JP.
Abstract : The discovery of potent thienoimidazole-based HCV NS5A inhibitors is herein reported. A novel method to access the thienoimidazole [5,5]-bicyclic system is disclosed. This method gave access to a common key intermediate (6) that was engaged in Suzuki or Sonogashira reactions with coupling partners bearing different linkers. A detailed study of the structure-activity relationship (SAR) of the linkers revealed that aromatic linkers with linear topologies are required to achieve high potency for both 1a and 1b HCV genotypes. Compound 20, with a para-phenyl linker, was identified as a potential lead displaying potencies of 17 and 8 pM against genotype 1a and 1b replicons, respectively.
|
Antiviral activity against Hepatitis C virus genotype 1b harboring NS5A Y93H mutant gene in Huh-luc/neo-ET replicon cells after 48 hrs by transient replicon mutant-based luciferase assay
|
Hepatitis C virus subtype 1b
|
0.3162
nM
|
|
Journal : J. Med. Chem.
Title : Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants: from lead to clinical compound.
Year : 2014
Volume : 57
Issue : 5
First Page : 2058
Last Page : 2073
Authors : Kazmierski WM, Maynard A, Duan M, Baskaran S, Botyanszki J, Crosby R, Dickerson S, Tallant M, Grimes R, Hamatake R, Leivers M, Roberts CD, Walker J.
Abstract : Rapid clinical progress of hepatitis C virus (HCV) replication inhibitors, including these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatment. Herein, we describe our explorations of diverse spiropyrrolidine motifs in novel NS5A inhibitors and a proposed interaction model. We discovered that the 1,4-dioxa-7-azaspiro[4.4]nonane motif in inhibitor 41H (GSK2236805) supported high potency against genotypes 1a and 1b as well as in genotype 1b L31V and Y93H mutants. Consistent with this, 41H potently suppressed HCV RNA in the 20-day RNA reduction assay. Pharmacokinetic and safety data supported further progression of 41H to the clinic.
|
Antiviral activity against Hepatitis C virus genotype 1b harboring NS5A L31V mutant gene in Huh-luc/neo-ET replicon cells after 48 hrs by transient replicon mutant-based luciferase assay
|
Hepatitis C virus subtype 1b
|
0.1259
nM
|
|
Journal : J. Med. Chem.
Title : Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants: from lead to clinical compound.
Year : 2014
Volume : 57
Issue : 5
First Page : 2058
Last Page : 2073
Authors : Kazmierski WM, Maynard A, Duan M, Baskaran S, Botyanszki J, Crosby R, Dickerson S, Tallant M, Grimes R, Hamatake R, Leivers M, Roberts CD, Walker J.
Abstract : Rapid clinical progress of hepatitis C virus (HCV) replication inhibitors, including these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatment. Herein, we describe our explorations of diverse spiropyrrolidine motifs in novel NS5A inhibitors and a proposed interaction model. We discovered that the 1,4-dioxa-7-azaspiro[4.4]nonane motif in inhibitor 41H (GSK2236805) supported high potency against genotypes 1a and 1b as well as in genotype 1b L31V and Y93H mutants. Consistent with this, 41H potently suppressed HCV RNA in the 20-day RNA reduction assay. Pharmacokinetic and safety data supported further progression of 41H to the clinic.
|
Antiviral activity against Hepatitis C virus genotype 1b harboring NS5A L28V mutant gene in Huh-luc/neo-ET replicon cells after 48 hrs by transient replicon mutant-based luciferase assay
|
Hepatitis C virus subtype 1b
|
0.003981
nM
|
|
Journal : J. Med. Chem.
Title : Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants: from lead to clinical compound.
Year : 2014
Volume : 57
Issue : 5
First Page : 2058
Last Page : 2073
Authors : Kazmierski WM, Maynard A, Duan M, Baskaran S, Botyanszki J, Crosby R, Dickerson S, Tallant M, Grimes R, Hamatake R, Leivers M, Roberts CD, Walker J.
Abstract : Rapid clinical progress of hepatitis C virus (HCV) replication inhibitors, including these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatment. Herein, we describe our explorations of diverse spiropyrrolidine motifs in novel NS5A inhibitors and a proposed interaction model. We discovered that the 1,4-dioxa-7-azaspiro[4.4]nonane motif in inhibitor 41H (GSK2236805) supported high potency against genotypes 1a and 1b as well as in genotype 1b L31V and Y93H mutants. Consistent with this, 41H potently suppressed HCV RNA in the 20-day RNA reduction assay. Pharmacokinetic and safety data supported further progression of 41H to the clinic.
|
Antiviral activity against Hepatitis C virus genotype 1b in Huh-luc/neo-ET replicon cells after 48 hrs by replicon-based luciferase assay
|
Hepatitis C virus subtype 1b
|
0.01
nM
|
|
Journal : J. Med. Chem.
Title : Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants: from lead to clinical compound.
Year : 2014
Volume : 57
Issue : 5
First Page : 2058
Last Page : 2073
Authors : Kazmierski WM, Maynard A, Duan M, Baskaran S, Botyanszki J, Crosby R, Dickerson S, Tallant M, Grimes R, Hamatake R, Leivers M, Roberts CD, Walker J.
Abstract : Rapid clinical progress of hepatitis C virus (HCV) replication inhibitors, including these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatment. Herein, we describe our explorations of diverse spiropyrrolidine motifs in novel NS5A inhibitors and a proposed interaction model. We discovered that the 1,4-dioxa-7-azaspiro[4.4]nonane motif in inhibitor 41H (GSK2236805) supported high potency against genotypes 1a and 1b as well as in genotype 1b L31V and Y93H mutants. Consistent with this, 41H potently suppressed HCV RNA in the 20-day RNA reduction assay. Pharmacokinetic and safety data supported further progression of 41H to the clinic.
|
Antiviral activity against Hepatitis C virus genotype 1a in Huh-luc/neo-ET replicon cells after 48 hrs by replicon-based luciferase assay
|
Hepatitis C virus subtype 1a
|
0.03981
nM
|
|
Journal : J. Med. Chem.
Title : Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants: from lead to clinical compound.
Year : 2014
Volume : 57
Issue : 5
First Page : 2058
Last Page : 2073
Authors : Kazmierski WM, Maynard A, Duan M, Baskaran S, Botyanszki J, Crosby R, Dickerson S, Tallant M, Grimes R, Hamatake R, Leivers M, Roberts CD, Walker J.
Abstract : Rapid clinical progress of hepatitis C virus (HCV) replication inhibitors, including these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatment. Herein, we describe our explorations of diverse spiropyrrolidine motifs in novel NS5A inhibitors and a proposed interaction model. We discovered that the 1,4-dioxa-7-azaspiro[4.4]nonane motif in inhibitor 41H (GSK2236805) supported high potency against genotypes 1a and 1b as well as in genotype 1b L31V and Y93H mutants. Consistent with this, 41H potently suppressed HCV RNA in the 20-day RNA reduction assay. Pharmacokinetic and safety data supported further progression of 41H to the clinic.
|
Antiviral activity against HCV6
|
Hepatitis C virus genotype 6
|
0.054
nM
|
|
Journal : J. Med. Chem.
Title : Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.
Year : 2014
Volume : 57
Issue : 5
First Page : 2013
Last Page : 2032
Authors : Belema M, Nguyen VN, Bachand C, Deon DH, Goodrich JT, James CA, Lavoie R, Lopez OD, Martel A, Romine JL, Ruediger EH, Snyder LB, St Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O'Boyle DR, Colonno RJ, Gao M, Meanwell NA, Hamann LG.
Abstract : The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
|
Antiviral activity against HCV5a
|
Hepatitis C virus subtype 5a
|
0.033
nM
|
|
Journal : J. Med. Chem.
Title : Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.
Year : 2014
Volume : 57
Issue : 5
First Page : 2013
Last Page : 2032
Authors : Belema M, Nguyen VN, Bachand C, Deon DH, Goodrich JT, James CA, Lavoie R, Lopez OD, Martel A, Romine JL, Ruediger EH, Snyder LB, St Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O'Boyle DR, Colonno RJ, Gao M, Meanwell NA, Hamann LG.
Abstract : The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
|
Antiviral activity against HCV4a
|
Hepatitis C virus subtype 4a
|
0.012
nM
|
|
Journal : J. Med. Chem.
Title : Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.
Year : 2014
Volume : 57
Issue : 5
First Page : 2013
Last Page : 2032
Authors : Belema M, Nguyen VN, Bachand C, Deon DH, Goodrich JT, James CA, Lavoie R, Lopez OD, Martel A, Romine JL, Ruediger EH, Snyder LB, St Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O'Boyle DR, Colonno RJ, Gao M, Meanwell NA, Hamann LG.
Abstract : The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
|
Antiviral activity against HCV3a YH
|
Hepatitis C virus subtype 3a
|
364.0
nM
|
|
Journal : J. Med. Chem.
Title : Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.
Year : 2014
Volume : 57
Issue : 5
First Page : 2013
Last Page : 2032
Authors : Belema M, Nguyen VN, Bachand C, Deon DH, Goodrich JT, James CA, Lavoie R, Lopez OD, Martel A, Romine JL, Ruediger EH, Snyder LB, St Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O'Boyle DR, Colonno RJ, Gao M, Meanwell NA, Hamann LG.
Abstract : The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
|
Antiviral activity against HCV3a
|
Hepatitis C virus subtype 3a
|
0.146
nM
|
|
Journal : J. Med. Chem.
Title : Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.
Year : 2014
Volume : 57
Issue : 5
First Page : 2013
Last Page : 2032
Authors : Belema M, Nguyen VN, Bachand C, Deon DH, Goodrich JT, James CA, Lavoie R, Lopez OD, Martel A, Romine JL, Ruediger EH, Snyder LB, St Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O'Boyle DR, Colonno RJ, Gao M, Meanwell NA, Hamann LG.
Abstract : The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
|
Antiviral activity against HCV2a J6
|
Hepatitis C virus subtype 2a
|
7.5
nM
|
|
Journal : J. Med. Chem.
Title : Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.
Year : 2014
Volume : 57
Issue : 5
First Page : 2013
Last Page : 2032
Authors : Belema M, Nguyen VN, Bachand C, Deon DH, Goodrich JT, James CA, Lavoie R, Lopez OD, Martel A, Romine JL, Ruediger EH, Snyder LB, St Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O'Boyle DR, Colonno RJ, Gao M, Meanwell NA, Hamann LG.
Abstract : The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
|
Antiviral activity against HCV2a JHF1
|
Hepatitis C virus JFH-1
|
0.071
nM
|
|
Journal : J. Med. Chem.
Title : Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.
Year : 2014
Volume : 57
Issue : 5
First Page : 2013
Last Page : 2032
Authors : Belema M, Nguyen VN, Bachand C, Deon DH, Goodrich JT, James CA, Lavoie R, Lopez OD, Martel A, Romine JL, Ruediger EH, Snyder LB, St Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O'Boyle DR, Colonno RJ, Gao M, Meanwell NA, Hamann LG.
Abstract : The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
|
Inhibition of sodium channel (unknown origin) assessed as channel conductance at 10 uM by whole cell patch clamp assay
|
Homo sapiens
|
51.0
%
|
|
Journal : J. Med. Chem.
Title : Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.
Year : 2014
Volume : 57
Issue : 5
First Page : 2013
Last Page : 2032
Authors : Belema M, Nguyen VN, Bachand C, Deon DH, Goodrich JT, James CA, Lavoie R, Lopez OD, Martel A, Romine JL, Ruediger EH, Snyder LB, St Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O'Boyle DR, Colonno RJ, Gao M, Meanwell NA, Hamann LG.
Abstract : The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
|
Antiviral activity against HCV1b infected in human HuH7 cells assessed as inhibition of viral replication after 72 hrs by FRET assay
|
Hepatitis C virus subtype 1b
|
0.009
nM
|
|
Journal : J. Med. Chem.
Title : Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.
Year : 2014
Volume : 57
Issue : 5
First Page : 2013
Last Page : 2032
Authors : Belema M, Nguyen VN, Bachand C, Deon DH, Goodrich JT, James CA, Lavoie R, Lopez OD, Martel A, Romine JL, Ruediger EH, Snyder LB, St Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O'Boyle DR, Colonno RJ, Gao M, Meanwell NA, Hamann LG.
Abstract : The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
|
Antiviral activity against HCV1a infected in human HuH7 cells assessed as inhibition of viral replication after 72 hrs by FRET assay
|
Hepatitis C virus subtype 1a
|
0.05
nM
|
|
Journal : J. Med. Chem.
Title : Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.
Year : 2014
Volume : 57
Issue : 5
First Page : 2013
Last Page : 2032
Authors : Belema M, Nguyen VN, Bachand C, Deon DH, Goodrich JT, James CA, Lavoie R, Lopez OD, Martel A, Romine JL, Ruediger EH, Snyder LB, St Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O'Boyle DR, Colonno RJ, Gao M, Meanwell NA, Hamann LG.
Abstract : The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
|
Antiviral activity against HCV genotype 1b Con1 infected in human HuH7 cells assessed as inhibition of viral RNA replication after 3 days by renilla luciferase reporter gene assay
|
Hepatitis C virus (isolate Con1)
|
0.009
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection.
Year : 2014
Volume : 57
Issue : 5
First Page : 2033
Last Page : 2046
Authors : Link JO, Taylor JG, Xu L, Mitchell M, Guo H, Liu H, Kato D, Kirschberg T, Sun J, Squires N, Parrish J, Keller T, Yang ZY, Yang C, Matles M, Wang Y, Wang K, Cheng G, Tian Y, Mogalian E, Mondou E, Cornpropst M, Perry J, Desai MC.
Abstract : A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.
|
Antiviral activity against HCV genotype 1a H77 infected in human HuH7 cells assessed as inhibition of viral RNA replication after 3 days by renilla luciferase reporter gene assay
|
Hepatitis C virus (isolate H77)
|
0.05
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection.
Year : 2014
Volume : 57
Issue : 5
First Page : 2033
Last Page : 2046
Authors : Link JO, Taylor JG, Xu L, Mitchell M, Guo H, Liu H, Kato D, Kirschberg T, Sun J, Squires N, Parrish J, Keller T, Yang ZY, Yang C, Matles M, Wang Y, Wang K, Cheng G, Tian Y, Mogalian E, Mondou E, Cornpropst M, Perry J, Desai MC.
Abstract : A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.
|
Antiviral activity against Hepatitis C virus genotype 1a
|
Hepatitis C virus subtype 1a
|
0.383
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect.
Year : 2014
Volume : 57
Issue : 12
First Page : 5057
Last Page : 5071
Authors : Belema M, Meanwell NA.
Abstract : The discovery and development of the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (6) provides a compelling example of the power of phenotypic screening to identify leads engaging novel targets in mechanistically unique ways. HCV NS5A replication complex inhibitors are pan-genotypic in spectrum, and this mechanistic class provides the most potent HCV inhibitors in vitro that have been described to date. Clinical trials with 6 demonstrated a potent effect on reducing plasma viral load and, in combination with mechanistically orthogonal HCV inhibitors, established the ability to cure even the most difficult infections without the need for immune stimulation. In this Drug Annotation, we describe the discovery of the original high-throughput screening lead 7 and the chemical conundrum and challenges resolved in optimizing to 6 as a clinical candidate and finally we summarize the results of select clinical studies.
|
Antiviral activity against Hepatitis C virus genotype 1a H77 replicon
|
Hepatitis C virus (isolate H77)
|
0.05
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect.
Year : 2014
Volume : 57
Issue : 12
First Page : 5057
Last Page : 5071
Authors : Belema M, Meanwell NA.
Abstract : The discovery and development of the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (6) provides a compelling example of the power of phenotypic screening to identify leads engaging novel targets in mechanistically unique ways. HCV NS5A replication complex inhibitors are pan-genotypic in spectrum, and this mechanistic class provides the most potent HCV inhibitors in vitro that have been described to date. Clinical trials with 6 demonstrated a potent effect on reducing plasma viral load and, in combination with mechanistically orthogonal HCV inhibitors, established the ability to cure even the most difficult infections without the need for immune stimulation. In this Drug Annotation, we describe the discovery of the original high-throughput screening lead 7 and the chemical conundrum and challenges resolved in optimizing to 6 as a clinical candidate and finally we summarize the results of select clinical studies.
|
Antiviral activity against Hepatitis C virus genotype 1b Con1 replicon
|
Hepatitis C virus (isolate Con1)
|
0.009
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect.
Year : 2014
Volume : 57
Issue : 12
First Page : 5057
Last Page : 5071
Authors : Belema M, Meanwell NA.
Abstract : The discovery and development of the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (6) provides a compelling example of the power of phenotypic screening to identify leads engaging novel targets in mechanistically unique ways. HCV NS5A replication complex inhibitors are pan-genotypic in spectrum, and this mechanistic class provides the most potent HCV inhibitors in vitro that have been described to date. Clinical trials with 6 demonstrated a potent effect on reducing plasma viral load and, in combination with mechanistically orthogonal HCV inhibitors, established the ability to cure even the most difficult infections without the need for immune stimulation. In this Drug Annotation, we describe the discovery of the original high-throughput screening lead 7 and the chemical conundrum and challenges resolved in optimizing to 6 as a clinical candidate and finally we summarize the results of select clinical studies.
|
Antiviral activity against Hepatitis C virus genotype 2a JFH-1 replicon
|
Hepatitis C virus JFH-1
|
0.071
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect.
Year : 2014
Volume : 57
Issue : 12
First Page : 5057
Last Page : 5071
Authors : Belema M, Meanwell NA.
Abstract : The discovery and development of the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (6) provides a compelling example of the power of phenotypic screening to identify leads engaging novel targets in mechanistically unique ways. HCV NS5A replication complex inhibitors are pan-genotypic in spectrum, and this mechanistic class provides the most potent HCV inhibitors in vitro that have been described to date. Clinical trials with 6 demonstrated a potent effect on reducing plasma viral load and, in combination with mechanistically orthogonal HCV inhibitors, established the ability to cure even the most difficult infections without the need for immune stimulation. In this Drug Annotation, we describe the discovery of the original high-throughput screening lead 7 and the chemical conundrum and challenges resolved in optimizing to 6 as a clinical candidate and finally we summarize the results of select clinical studies.
|
Antiviral activity against Hepatitis C virus genotype 2a J6 replicon containing Hepatitis C virus genotype 2a JFH-1 replicon
|
Hepatitis C virus subtype 2a
|
7.5
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect.
Year : 2014
Volume : 57
Issue : 12
First Page : 5057
Last Page : 5071
Authors : Belema M, Meanwell NA.
Abstract : The discovery and development of the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (6) provides a compelling example of the power of phenotypic screening to identify leads engaging novel targets in mechanistically unique ways. HCV NS5A replication complex inhibitors are pan-genotypic in spectrum, and this mechanistic class provides the most potent HCV inhibitors in vitro that have been described to date. Clinical trials with 6 demonstrated a potent effect on reducing plasma viral load and, in combination with mechanistically orthogonal HCV inhibitors, established the ability to cure even the most difficult infections without the need for immune stimulation. In this Drug Annotation, we describe the discovery of the original high-throughput screening lead 7 and the chemical conundrum and challenges resolved in optimizing to 6 as a clinical candidate and finally we summarize the results of select clinical studies.
|
Antiviral activity against Hepatitis C virus genotype 3a replicon
|
Hepatitis C virus subtype 3a
|
0.146
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect.
Year : 2014
Volume : 57
Issue : 12
First Page : 5057
Last Page : 5071
Authors : Belema M, Meanwell NA.
Abstract : The discovery and development of the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (6) provides a compelling example of the power of phenotypic screening to identify leads engaging novel targets in mechanistically unique ways. HCV NS5A replication complex inhibitors are pan-genotypic in spectrum, and this mechanistic class provides the most potent HCV inhibitors in vitro that have been described to date. Clinical trials with 6 demonstrated a potent effect on reducing plasma viral load and, in combination with mechanistically orthogonal HCV inhibitors, established the ability to cure even the most difficult infections without the need for immune stimulation. In this Drug Annotation, we describe the discovery of the original high-throughput screening lead 7 and the chemical conundrum and challenges resolved in optimizing to 6 as a clinical candidate and finally we summarize the results of select clinical studies.
|
Antiviral activity against Hepatitis C virus genotype 3a Y-H replicon containing Hepatitis C virus genotype 1b Con1 replicon
|
Hepatitis C virus subtype 3a
|
364.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect.
Year : 2014
Volume : 57
Issue : 12
First Page : 5057
Last Page : 5071
Authors : Belema M, Meanwell NA.
Abstract : The discovery and development of the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (6) provides a compelling example of the power of phenotypic screening to identify leads engaging novel targets in mechanistically unique ways. HCV NS5A replication complex inhibitors are pan-genotypic in spectrum, and this mechanistic class provides the most potent HCV inhibitors in vitro that have been described to date. Clinical trials with 6 demonstrated a potent effect on reducing plasma viral load and, in combination with mechanistically orthogonal HCV inhibitors, established the ability to cure even the most difficult infections without the need for immune stimulation. In this Drug Annotation, we describe the discovery of the original high-throughput screening lead 7 and the chemical conundrum and challenges resolved in optimizing to 6 as a clinical candidate and finally we summarize the results of select clinical studies.
|
Antiviral activity against Hepatitis C virus genotype 4a replicon containing Hepatitis C virus genotype 1b Con1 replicon
|
Hepatitis C virus subtype 4a
|
0.012
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect.
Year : 2014
Volume : 57
Issue : 12
First Page : 5057
Last Page : 5071
Authors : Belema M, Meanwell NA.
Abstract : The discovery and development of the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (6) provides a compelling example of the power of phenotypic screening to identify leads engaging novel targets in mechanistically unique ways. HCV NS5A replication complex inhibitors are pan-genotypic in spectrum, and this mechanistic class provides the most potent HCV inhibitors in vitro that have been described to date. Clinical trials with 6 demonstrated a potent effect on reducing plasma viral load and, in combination with mechanistically orthogonal HCV inhibitors, established the ability to cure even the most difficult infections without the need for immune stimulation. In this Drug Annotation, we describe the discovery of the original high-throughput screening lead 7 and the chemical conundrum and challenges resolved in optimizing to 6 as a clinical candidate and finally we summarize the results of select clinical studies.
|
Antiviral activity against Hepatitis C virus genotype 5a replicon containing Hepatitis C virus genotype 2a JFH-1 replicon
|
Hepatitis C virus subtype 5a
|
0.033
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect.
Year : 2014
Volume : 57
Issue : 12
First Page : 5057
Last Page : 5071
Authors : Belema M, Meanwell NA.
Abstract : The discovery and development of the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (6) provides a compelling example of the power of phenotypic screening to identify leads engaging novel targets in mechanistically unique ways. HCV NS5A replication complex inhibitors are pan-genotypic in spectrum, and this mechanistic class provides the most potent HCV inhibitors in vitro that have been described to date. Clinical trials with 6 demonstrated a potent effect on reducing plasma viral load and, in combination with mechanistically orthogonal HCV inhibitors, established the ability to cure even the most difficult infections without the need for immune stimulation. In this Drug Annotation, we describe the discovery of the original high-throughput screening lead 7 and the chemical conundrum and challenges resolved in optimizing to 6 as a clinical candidate and finally we summarize the results of select clinical studies.
|
Antiviral activity against Hepatitis C virus genotype 6a replicon containing Hepatitis C virus genotype 2a JFH-1 replicon
|
Hepatitis C virus subtype 6a
|
0.054
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect.
Year : 2014
Volume : 57
Issue : 12
First Page : 5057
Last Page : 5071
Authors : Belema M, Meanwell NA.
Abstract : The discovery and development of the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (6) provides a compelling example of the power of phenotypic screening to identify leads engaging novel targets in mechanistically unique ways. HCV NS5A replication complex inhibitors are pan-genotypic in spectrum, and this mechanistic class provides the most potent HCV inhibitors in vitro that have been described to date. Clinical trials with 6 demonstrated a potent effect on reducing plasma viral load and, in combination with mechanistically orthogonal HCV inhibitors, established the ability to cure even the most difficult infections without the need for immune stimulation. In this Drug Annotation, we describe the discovery of the original high-throughput screening lead 7 and the chemical conundrum and challenges resolved in optimizing to 6 as a clinical candidate and finally we summarize the results of select clinical studies.
|
Antiviral activity against Hepatitis C virus genotype 2a JFH
|
Hepatitis C virus JFH-1
|
0.028
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect.
Year : 2014
Volume : 57
Issue : 12
First Page : 5057
Last Page : 5071
Authors : Belema M, Meanwell NA.
Abstract : The discovery and development of the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (6) provides a compelling example of the power of phenotypic screening to identify leads engaging novel targets in mechanistically unique ways. HCV NS5A replication complex inhibitors are pan-genotypic in spectrum, and this mechanistic class provides the most potent HCV inhibitors in vitro that have been described to date. Clinical trials with 6 demonstrated a potent effect on reducing plasma viral load and, in combination with mechanistically orthogonal HCV inhibitors, established the ability to cure even the most difficult infections without the need for immune stimulation. In this Drug Annotation, we describe the discovery of the original high-throughput screening lead 7 and the chemical conundrum and challenges resolved in optimizing to 6 as a clinical candidate and finally we summarize the results of select clinical studies.
|
Inhibition of NS5A in HCV genotype-1a infected in human HuH7 cells by luciferase reporter gene assay
|
Hepatitis C virus subtype 1a
|
0.14
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of functionalized bisimidazoles bearing cyclic aliphatic-phenyl motifs as HCV NS5A inhibitors.
Year : 2014
Volume : 24
Issue : 24
First Page : 5731
Last Page : 5737
Authors : Zhong M, Peng E, Huang N, Huang Q, Huq A, Lau M, Colonno R, Li L.
Abstract : This Letter describes the discovery of a number of functionalized bisimidazoles bearing a cyclohexylphenyl, piperidylphenyl, or bicyclo[2,2,2]octylphenyl motif as HCV NS5A inhibitors. Compounds 2c, 4b and 6 have demonstrated low single-digit nM potency in gt-1a replicon and double-digit pM potency in gt-1b replicon, respectively. Moreover, both 4b and 6 have, respectively, exhibited good oral bioavailability in rats with a favorable liver/plasma ratio of the drug concentration.
|
Inhibition of NS5A in HCV genotype-1b infected in human HuH7 cells by luciferase reporter gene assay
|
Hepatitis C virus subtype 1b
|
0.023
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of functionalized bisimidazoles bearing cyclic aliphatic-phenyl motifs as HCV NS5A inhibitors.
Year : 2014
Volume : 24
Issue : 24
First Page : 5731
Last Page : 5737
Authors : Zhong M, Peng E, Huang N, Huang Q, Huq A, Lau M, Colonno R, Li L.
Abstract : This Letter describes the discovery of a number of functionalized bisimidazoles bearing a cyclohexylphenyl, piperidylphenyl, or bicyclo[2,2,2]octylphenyl motif as HCV NS5A inhibitors. Compounds 2c, 4b and 6 have demonstrated low single-digit nM potency in gt-1a replicon and double-digit pM potency in gt-1b replicon, respectively. Moreover, both 4b and 6 have, respectively, exhibited good oral bioavailability in rats with a favorable liver/plasma ratio of the drug concentration.
|
Antiviral activity against HCV genotype 1a infected in human HuH7 cells by luciferase reporter gene assay
|
Hepatitis C virus subtype 1a
|
0.14
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent bisimidazole-based HCV NS5A inhibitors bearing annulated tricyclic motifs.
Year : 2014
Volume : 24
Issue : 24
First Page : 5738
Last Page : 5742
Authors : Zhong M, Peng E, Huang N, Huang Q, Huq A, Lau M, Colonno R, Li L.
Abstract : This Letter describes the synthesis and biological evaluation of a number of functionalized bisimidazoles bearing annulated tricyclic motifs as potent inhibitors of HCV NS5A protein. Compound 4 h, which contains a substituted tricyclic 6-6-6 xanthene, demonstrated broad genotypic spectrum, compelling potency, and good oral bioavailability with dose-dependent drug exposure level in multiple animal species.
|
Antiviral activity against HCV genotype 1b infected in human HuH7 cells by luciferase reporter gene assay
|
Hepatitis C virus subtype 1b
|
0.073
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent bisimidazole-based HCV NS5A inhibitors bearing annulated tricyclic motifs.
Year : 2014
Volume : 24
Issue : 24
First Page : 5738
Last Page : 5742
Authors : Zhong M, Peng E, Huang N, Huang Q, Huq A, Lau M, Colonno R, Li L.
Abstract : This Letter describes the synthesis and biological evaluation of a number of functionalized bisimidazoles bearing annulated tricyclic motifs as potent inhibitors of HCV NS5A protein. Compound 4 h, which contains a substituted tricyclic 6-6-6 xanthene, demonstrated broad genotypic spectrum, compelling potency, and good oral bioavailability with dose-dependent drug exposure level in multiple animal species.
|
Antiviral activity against HCV genotype 3a infected in human HuH7 cells by luciferase reporter gene assay
|
Hepatitis C virus subtype 3a
|
0.67
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent bisimidazole-based HCV NS5A inhibitors bearing annulated tricyclic motifs.
Year : 2014
Volume : 24
Issue : 24
First Page : 5738
Last Page : 5742
Authors : Zhong M, Peng E, Huang N, Huang Q, Huq A, Lau M, Colonno R, Li L.
Abstract : This Letter describes the synthesis and biological evaluation of a number of functionalized bisimidazoles bearing annulated tricyclic motifs as potent inhibitors of HCV NS5A protein. Compound 4 h, which contains a substituted tricyclic 6-6-6 xanthene, demonstrated broad genotypic spectrum, compelling potency, and good oral bioavailability with dose-dependent drug exposure level in multiple animal species.
|
Antiviral activity against wild type HCV genotype 1b assessed as replication level
|
Hepatitis C virus subtype 1b
|
0.0026
nM
|
|
Journal : J. Med. Chem.
Title : Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition.
Year : 2014
Volume : 57
Issue : 23
First Page : 10031
Last Page : 10043
Authors : Nettles JH, Stanton RA, Broyde J, Amblard F, Zhang H, Zhou L, Shi J, McBrayer TR, Whitaker T, Coats SJ, Kohler JJ, Schinazi RF.
Abstract : Symmetric, dimeric daclatasvir (BMS-790052) is the clinical lead for a class of picomolar inhibitors of HCV replication. While specific, resistance-bearing mutations at positions 31 and 93 of domain I strongly suggest the viral NS5A as target, structural mechanism(s) for the drugs' activities and resistance remains unclear. Several previous models suggested symmetric binding modes relative to the homodimeric target; however, none can fully explain SAR details for this class. We present semiautomated workflows to model potential receptor conformations for docking. Surprisingly, ranking docked hits with our library-derived 3D-pharmacophore revealed two distinct asymmetric binding modes, at a conserved poly-proline region between 31 and 93, consistent with SAR. Interfering with protein-protein interactions at this membrane interface can explain potent inhibition of replication-complex formation, resistance, effects on lipid droplet distribution, and virion release. These detailed interaction models and proposed mechanisms of action will allow structure-based design of new NS5A directed compounds with higher barriers to HCV resistance.
|
Antiviral activity against HCV genotype 1b expressing NS5A L31M mutant assessed as replication level
|
Hepatitis C virus subtype 1b
|
0.0084
nM
|
|
Journal : J. Med. Chem.
Title : Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition.
Year : 2014
Volume : 57
Issue : 23
First Page : 10031
Last Page : 10043
Authors : Nettles JH, Stanton RA, Broyde J, Amblard F, Zhang H, Zhou L, Shi J, McBrayer TR, Whitaker T, Coats SJ, Kohler JJ, Schinazi RF.
Abstract : Symmetric, dimeric daclatasvir (BMS-790052) is the clinical lead for a class of picomolar inhibitors of HCV replication. While specific, resistance-bearing mutations at positions 31 and 93 of domain I strongly suggest the viral NS5A as target, structural mechanism(s) for the drugs' activities and resistance remains unclear. Several previous models suggested symmetric binding modes relative to the homodimeric target; however, none can fully explain SAR details for this class. We present semiautomated workflows to model potential receptor conformations for docking. Surprisingly, ranking docked hits with our library-derived 3D-pharmacophore revealed two distinct asymmetric binding modes, at a conserved poly-proline region between 31 and 93, consistent with SAR. Interfering with protein-protein interactions at this membrane interface can explain potent inhibition of replication-complex formation, resistance, effects on lipid droplet distribution, and virion release. These detailed interaction models and proposed mechanisms of action will allow structure-based design of new NS5A directed compounds with higher barriers to HCV resistance.
|
Antiviral activity against HCV genotype 1b expressing NS5A L31V mutant assessed as replication level
|
Hepatitis C virus subtype 1b
|
0.0717
nM
|
|
Journal : J. Med. Chem.
Title : Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition.
Year : 2014
Volume : 57
Issue : 23
First Page : 10031
Last Page : 10043
Authors : Nettles JH, Stanton RA, Broyde J, Amblard F, Zhang H, Zhou L, Shi J, McBrayer TR, Whitaker T, Coats SJ, Kohler JJ, Schinazi RF.
Abstract : Symmetric, dimeric daclatasvir (BMS-790052) is the clinical lead for a class of picomolar inhibitors of HCV replication. While specific, resistance-bearing mutations at positions 31 and 93 of domain I strongly suggest the viral NS5A as target, structural mechanism(s) for the drugs' activities and resistance remains unclear. Several previous models suggested symmetric binding modes relative to the homodimeric target; however, none can fully explain SAR details for this class. We present semiautomated workflows to model potential receptor conformations for docking. Surprisingly, ranking docked hits with our library-derived 3D-pharmacophore revealed two distinct asymmetric binding modes, at a conserved poly-proline region between 31 and 93, consistent with SAR. Interfering with protein-protein interactions at this membrane interface can explain potent inhibition of replication-complex formation, resistance, effects on lipid droplet distribution, and virion release. These detailed interaction models and proposed mechanisms of action will allow structure-based design of new NS5A directed compounds with higher barriers to HCV resistance.
|
Antiviral activity against HCV genotype 1b expressing NS5A Y93H mutant assessed as replication level
|
Hepatitis C virus subtype 1b
|
0.0623
nM
|
|
Journal : J. Med. Chem.
Title : Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition.
Year : 2014
Volume : 57
Issue : 23
First Page : 10031
Last Page : 10043
Authors : Nettles JH, Stanton RA, Broyde J, Amblard F, Zhang H, Zhou L, Shi J, McBrayer TR, Whitaker T, Coats SJ, Kohler JJ, Schinazi RF.
Abstract : Symmetric, dimeric daclatasvir (BMS-790052) is the clinical lead for a class of picomolar inhibitors of HCV replication. While specific, resistance-bearing mutations at positions 31 and 93 of domain I strongly suggest the viral NS5A as target, structural mechanism(s) for the drugs' activities and resistance remains unclear. Several previous models suggested symmetric binding modes relative to the homodimeric target; however, none can fully explain SAR details for this class. We present semiautomated workflows to model potential receptor conformations for docking. Surprisingly, ranking docked hits with our library-derived 3D-pharmacophore revealed two distinct asymmetric binding modes, at a conserved poly-proline region between 31 and 93, consistent with SAR. Interfering with protein-protein interactions at this membrane interface can explain potent inhibition of replication-complex formation, resistance, effects on lipid droplet distribution, and virion release. These detailed interaction models and proposed mechanisms of action will allow structure-based design of new NS5A directed compounds with higher barriers to HCV resistance.
|
Antiviral activity against HCV genotype 1b expressing NS5A L31M/Y93H mutant assessed as replication level
|
Hepatitis C virus subtype 1b
|
18.27
nM
|
|
Journal : J. Med. Chem.
Title : Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition.
Year : 2014
Volume : 57
Issue : 23
First Page : 10031
Last Page : 10043
Authors : Nettles JH, Stanton RA, Broyde J, Amblard F, Zhang H, Zhou L, Shi J, McBrayer TR, Whitaker T, Coats SJ, Kohler JJ, Schinazi RF.
Abstract : Symmetric, dimeric daclatasvir (BMS-790052) is the clinical lead for a class of picomolar inhibitors of HCV replication. While specific, resistance-bearing mutations at positions 31 and 93 of domain I strongly suggest the viral NS5A as target, structural mechanism(s) for the drugs' activities and resistance remains unclear. Several previous models suggested symmetric binding modes relative to the homodimeric target; however, none can fully explain SAR details for this class. We present semiautomated workflows to model potential receptor conformations for docking. Surprisingly, ranking docked hits with our library-derived 3D-pharmacophore revealed two distinct asymmetric binding modes, at a conserved poly-proline region between 31 and 93, consistent with SAR. Interfering with protein-protein interactions at this membrane interface can explain potent inhibition of replication-complex formation, resistance, effects on lipid droplet distribution, and virion release. These detailed interaction models and proposed mechanisms of action will allow structure-based design of new NS5A directed compounds with higher barriers to HCV resistance.
|
Antiviral activity against HCV genotype 1b expressing NS5A L31V/Y93H mutant assessed as replication level
|
Hepatitis C virus subtype 1b
|
38.03
nM
|
|
Journal : J. Med. Chem.
Title : Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition.
Year : 2014
Volume : 57
Issue : 23
First Page : 10031
Last Page : 10043
Authors : Nettles JH, Stanton RA, Broyde J, Amblard F, Zhang H, Zhou L, Shi J, McBrayer TR, Whitaker T, Coats SJ, Kohler JJ, Schinazi RF.
Abstract : Symmetric, dimeric daclatasvir (BMS-790052) is the clinical lead for a class of picomolar inhibitors of HCV replication. While specific, resistance-bearing mutations at positions 31 and 93 of domain I strongly suggest the viral NS5A as target, structural mechanism(s) for the drugs' activities and resistance remains unclear. Several previous models suggested symmetric binding modes relative to the homodimeric target; however, none can fully explain SAR details for this class. We present semiautomated workflows to model potential receptor conformations for docking. Surprisingly, ranking docked hits with our library-derived 3D-pharmacophore revealed two distinct asymmetric binding modes, at a conserved poly-proline region between 31 and 93, consistent with SAR. Interfering with protein-protein interactions at this membrane interface can explain potent inhibition of replication-complex formation, resistance, effects on lipid droplet distribution, and virion release. These detailed interaction models and proposed mechanisms of action will allow structure-based design of new NS5A directed compounds with higher barriers to HCV resistance.
|
Antiviral activity against HCV genotype 4a infected in human HuH7 cells by luciferase reporter gene assay
|
Hepatitis C virus subtype 4a
|
0.41
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent bisimidazole-based HCV NS5A inhibitors bearing annulated tricyclic motifs.
Year : 2014
Volume : 24
Issue : 24
First Page : 5738
Last Page : 5742
Authors : Zhong M, Peng E, Huang N, Huang Q, Huq A, Lau M, Colonno R, Li L.
Abstract : This Letter describes the synthesis and biological evaluation of a number of functionalized bisimidazoles bearing annulated tricyclic motifs as potent inhibitors of HCV NS5A protein. Compound 4 h, which contains a substituted tricyclic 6-6-6 xanthene, demonstrated broad genotypic spectrum, compelling potency, and good oral bioavailability with dose-dependent drug exposure level in multiple animal species.
|
Antiviral activity against HCV genotype 5a infected in human HuH7 cells by luciferase reporter gene assay
|
Hepatitis C virus subtype 5a
|
0.051
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent bisimidazole-based HCV NS5A inhibitors bearing annulated tricyclic motifs.
Year : 2014
Volume : 24
Issue : 24
First Page : 5738
Last Page : 5742
Authors : Zhong M, Peng E, Huang N, Huang Q, Huq A, Lau M, Colonno R, Li L.
Abstract : This Letter describes the synthesis and biological evaluation of a number of functionalized bisimidazoles bearing annulated tricyclic motifs as potent inhibitors of HCV NS5A protein. Compound 4 h, which contains a substituted tricyclic 6-6-6 xanthene, demonstrated broad genotypic spectrum, compelling potency, and good oral bioavailability with dose-dependent drug exposure level in multiple animal species.
|
Antiviral activity against HCV genotype 6a infected in human HuH7 cells by luciferase reporter gene assay
|
Hepatitis C virus subtype 6a
|
0.45
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent bisimidazole-based HCV NS5A inhibitors bearing annulated tricyclic motifs.
Year : 2014
Volume : 24
Issue : 24
First Page : 5738
Last Page : 5742
Authors : Zhong M, Peng E, Huang N, Huang Q, Huq A, Lau M, Colonno R, Li L.
Abstract : This Letter describes the synthesis and biological evaluation of a number of functionalized bisimidazoles bearing annulated tricyclic motifs as potent inhibitors of HCV NS5A protein. Compound 4 h, which contains a substituted tricyclic 6-6-6 xanthene, demonstrated broad genotypic spectrum, compelling potency, and good oral bioavailability with dose-dependent drug exposure level in multiple animal species.
|
Antiviral activity against HCV genotype 2a infected in human HuH7 cells by luciferase reporter gene assay
|
Hepatitis C virus subtype 2a
|
0.67
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent bisimidazole-based HCV NS5A inhibitors bearing annulated tricyclic motifs.
Year : 2014
Volume : 24
Issue : 24
First Page : 5738
Last Page : 5742
Authors : Zhong M, Peng E, Huang N, Huang Q, Huq A, Lau M, Colonno R, Li L.
Abstract : This Letter describes the synthesis and biological evaluation of a number of functionalized bisimidazoles bearing annulated tricyclic motifs as potent inhibitors of HCV NS5A protein. Compound 4 h, which contains a substituted tricyclic 6-6-6 xanthene, demonstrated broad genotypic spectrum, compelling potency, and good oral bioavailability with dose-dependent drug exposure level in multiple animal species.
|
Antiviral activity against HCV genotype 1b infected in human Huh7 cells after 3 days by cell-based replicon assay
|
Hepatitis C virus subtype 1b
|
0.003
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel highly potent hepatitis C virus NS5A inhibitor (AV4025).
Year : 2014
Volume : 57
Issue : 18
First Page : 7716
Last Page : 7730
Authors : Ivachtchenko AV, Mitkin OD, Yamanushkin PM, Kuznetsova IV, Bulanova EA, Shevkun NA, Koryakova AG, Karapetian RN, Bichko VV, Trifelenkov AS, Kravchenko DV, Vostokova NV, Veselov MS, Chufarova NV, Ivanenkov YA.
Abstract : A series of next in class small-molecule hepatitis C virus (HCV) NS5A inhibitors with picomolar potency containing 2-pyrrolidin-2-yl-5-{4-[4-(2-pyrrolidin-2-yl-1H-imidazol-5-yl)buta-1,3-diynyl]phenyl}-1H-imidazole cores was designed based on the SAR studies available for the reported NS5A inhibitors. Compound 13a (AV4025), with (S,S,S,S)-stereochemistry (EC50 = 3.4 ± 0.2 pM, HCV replicon genotype 1b), was dramatically more active than were the compounds with two (S)- and two (R)-chiral centers. Human serum did not significantly reduce the antiviral activity (<4-fold). Relatively favorable pharmacokinetic features and good oral bioavailability were observed during animal studies. Compound 13a was well tolerated in rodents (in mice, LD50 = 2326 mg/kg or higher), providing a relatively high therapeutic index. During safety, pharmacology and subchronic toxicity studies in rats and dogs, it was not associated with any significant pathological or clinical findings. This compound is currently being evaluated in phase I/II clinical trials for the treatment of HCV infection.
|
Antiviral activity against HCV genotype 1b Con1 infected in human HuH7 cells assessed as inhibition of viral replication
|
Hepatitis C virus (isolate Con1)
|
0.009
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of imidazole N-H substituted amide prodrugs as inhibitors of hepatitis C virus replication.
Year : 2015
Volume : 25
Issue : 16
First Page : 3147
Last Page : 3150
Authors : Zong X, Cai J, Chen J, Wang P, Zhou G, Chen B, Li W, Ji M.
Abstract : Twenty-five novel imidazole N-H substituted Daclatasvir (BMS-790052, DCV) analogues (8a-8y) were designed and synthesized as potential prodrugs. Structure modifications were performed in order to improve potency and pharmacokinetic (PK) properties. All target compounds were evaluated in a hepatitis C virus (HCV) genotype 1b replicon, and the 2-oxoethyl acetate substituted compound 8t showed similar anti-HCV activity (EC50 = 0.08 nM) to that of the lead compound Daclatasvir. Moreover, the utility of prodrug 8t was demonstrated through similar exposure of the parent compound when the prodrugs were dosed in vivo. PK studies showed that prodrug 8t was an ideal candidate for a slower and sustained release form of Daclatasvir.
|
Antiviral activity against HCV genotype 1b JFH-1 infected in human HuH7 cells assessed as inhibition of viral replication
|
Hepatitis C virus JFH-1
|
0.028
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of imidazole N-H substituted amide prodrugs as inhibitors of hepatitis C virus replication.
Year : 2015
Volume : 25
Issue : 16
First Page : 3147
Last Page : 3150
Authors : Zong X, Cai J, Chen J, Wang P, Zhou G, Chen B, Li W, Ji M.
Abstract : Twenty-five novel imidazole N-H substituted Daclatasvir (BMS-790052, DCV) analogues (8a-8y) were designed and synthesized as potential prodrugs. Structure modifications were performed in order to improve potency and pharmacokinetic (PK) properties. All target compounds were evaluated in a hepatitis C virus (HCV) genotype 1b replicon, and the 2-oxoethyl acetate substituted compound 8t showed similar anti-HCV activity (EC50 = 0.08 nM) to that of the lead compound Daclatasvir. Moreover, the utility of prodrug 8t was demonstrated through similar exposure of the parent compound when the prodrugs were dosed in vivo. PK studies showed that prodrug 8t was an ideal candidate for a slower and sustained release form of Daclatasvir.
|
Antiviral activity against HCV genotype 1b infected in human HuH7 cells assessed as reduction in viral RNA replication
|
Hepatitis C virus subtype 1b
|
0.004
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of novel anti-HCV molecules that deliver intracellularly three highly potent NS5A inhibitors.
Year : 2015
Volume : 25
Issue : 17
First Page : 3711
Last Page : 3715
Authors : Boucle S, Tao S, Amblard F, Stanton RA, Nettles JH, Li C, McBrayer TR, Whitaker T, Coats SJ, Schinazi RF.
Abstract : The design and synthesis of new non-symmetrical NS5A inhibitors with sulfur containing amino acids is reported along with their ability to block HCV replication in an HCV 1b replicon system. These compounds display EC50 values in the picomolar range with a large therapeutic index (>10(6)). Moreover, cellular pharmacology studies show that our preferred compounds intracellularly deliver three potent NS5A inhibitors.
|
Antiviral activity against HCV genotype 1a
|
Hepatitis C virus subtype 1a
|
0.048
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of novel anti-HCV molecules that deliver intracellularly three highly potent NS5A inhibitors.
Year : 2015
Volume : 25
Issue : 17
First Page : 3711
Last Page : 3715
Authors : Boucle S, Tao S, Amblard F, Stanton RA, Nettles JH, Li C, McBrayer TR, Whitaker T, Coats SJ, Schinazi RF.
Abstract : The design and synthesis of new non-symmetrical NS5A inhibitors with sulfur containing amino acids is reported along with their ability to block HCV replication in an HCV 1b replicon system. These compounds display EC50 values in the picomolar range with a large therapeutic index (>10(6)). Moreover, cellular pharmacology studies show that our preferred compounds intracellularly deliver three potent NS5A inhibitors.
|
Antiviral activity against HCV genotype 2a
|
Hepatitis C virus subtype 2a
|
0.024
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of novel anti-HCV molecules that deliver intracellularly three highly potent NS5A inhibitors.
Year : 2015
Volume : 25
Issue : 17
First Page : 3711
Last Page : 3715
Authors : Boucle S, Tao S, Amblard F, Stanton RA, Nettles JH, Li C, McBrayer TR, Whitaker T, Coats SJ, Schinazi RF.
Abstract : The design and synthesis of new non-symmetrical NS5A inhibitors with sulfur containing amino acids is reported along with their ability to block HCV replication in an HCV 1b replicon system. These compounds display EC50 values in the picomolar range with a large therapeutic index (>10(6)). Moreover, cellular pharmacology studies show that our preferred compounds intracellularly deliver three potent NS5A inhibitors.
|
Antiviral activity against wild type HCV genotype 1b infected in human HuH7 cells assessed as reduction in viral RNA replication
|
Hepatitis C virus subtype 1b
|
0.048
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of novel anti-HCV molecules that deliver intracellularly three highly potent NS5A inhibitors.
Year : 2015
Volume : 25
Issue : 17
First Page : 3711
Last Page : 3715
Authors : Boucle S, Tao S, Amblard F, Stanton RA, Nettles JH, Li C, McBrayer TR, Whitaker T, Coats SJ, Schinazi RF.
Abstract : The design and synthesis of new non-symmetrical NS5A inhibitors with sulfur containing amino acids is reported along with their ability to block HCV replication in an HCV 1b replicon system. These compounds display EC50 values in the picomolar range with a large therapeutic index (>10(6)). Moreover, cellular pharmacology studies show that our preferred compounds intracellularly deliver three potent NS5A inhibitors.
|
Antiviral activity against HCV genotype 1b expressing NS5A L31V mutant infected in human HuH7 cells assessed as reduction in viral RNA replication
|
Hepatitis C virus subtype 1b
|
0.035
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of novel anti-HCV molecules that deliver intracellularly three highly potent NS5A inhibitors.
Year : 2015
Volume : 25
Issue : 17
First Page : 3711
Last Page : 3715
Authors : Boucle S, Tao S, Amblard F, Stanton RA, Nettles JH, Li C, McBrayer TR, Whitaker T, Coats SJ, Schinazi RF.
Abstract : The design and synthesis of new non-symmetrical NS5A inhibitors with sulfur containing amino acids is reported along with their ability to block HCV replication in an HCV 1b replicon system. These compounds display EC50 values in the picomolar range with a large therapeutic index (>10(6)). Moreover, cellular pharmacology studies show that our preferred compounds intracellularly deliver three potent NS5A inhibitors.
|
Antiviral activity against HCV genotype 1b expressing NS5A Y93H mutant infected in human HuH7 cells assessed as reduction in viral RNA replication
|
Hepatitis C virus subtype 1b
|
0.18
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of novel anti-HCV molecules that deliver intracellularly three highly potent NS5A inhibitors.
Year : 2015
Volume : 25
Issue : 17
First Page : 3711
Last Page : 3715
Authors : Boucle S, Tao S, Amblard F, Stanton RA, Nettles JH, Li C, McBrayer TR, Whitaker T, Coats SJ, Schinazi RF.
Abstract : The design and synthesis of new non-symmetrical NS5A inhibitors with sulfur containing amino acids is reported along with their ability to block HCV replication in an HCV 1b replicon system. These compounds display EC50 values in the picomolar range with a large therapeutic index (>10(6)). Moreover, cellular pharmacology studies show that our preferred compounds intracellularly deliver three potent NS5A inhibitors.
|
Antiviral activity against HCV genotype 1a by replicon assay
|
Hepatitis C virus subtype 1a
|
0.05
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of silyl proline containing HCV NS5A inhibitors with pan-genotype activity: SAR development.
Year : 2016
Volume : 26
Issue : 5
First Page : 1475
Last Page : 1479
Authors : Nair AG, Zeng Q, Selyutin O, Rosenblum SB, Jiang Y, Yang DY, Keertikar K, Zhou G, Dwyer MP, Kim SH, Shankar B, Yu W, Tong L, Chen L, Mazzola R, Caldwell J, Tang H, Allard ML, Buckle RN, Gauuan PJ, Holst CL, Martin GS, Naicker KP, Vellekoop S, Agrawal S, Liu R, Kong R, Ingravallo P, Xia E, Zhai Y, Nomeir A, Kozlowski JA.
Abstract : HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.
|
Antiviral activity against HCV genotype 1b by replicon assay
|
Hepatitis C virus subtype 1b
|
0.01
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of silyl proline containing HCV NS5A inhibitors with pan-genotype activity: SAR development.
Year : 2016
Volume : 26
Issue : 5
First Page : 1475
Last Page : 1479
Authors : Nair AG, Zeng Q, Selyutin O, Rosenblum SB, Jiang Y, Yang DY, Keertikar K, Zhou G, Dwyer MP, Kim SH, Shankar B, Yu W, Tong L, Chen L, Mazzola R, Caldwell J, Tang H, Allard ML, Buckle RN, Gauuan PJ, Holst CL, Martin GS, Naicker KP, Vellekoop S, Agrawal S, Liu R, Kong R, Ingravallo P, Xia E, Zhai Y, Nomeir A, Kozlowski JA.
Abstract : HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.
|
Antiviral activity against HCV genotype 2a by replicon assay
|
Hepatitis C virus subtype 2a
|
0.04
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of silyl proline containing HCV NS5A inhibitors with pan-genotype activity: SAR development.
Year : 2016
Volume : 26
Issue : 5
First Page : 1475
Last Page : 1479
Authors : Nair AG, Zeng Q, Selyutin O, Rosenblum SB, Jiang Y, Yang DY, Keertikar K, Zhou G, Dwyer MP, Kim SH, Shankar B, Yu W, Tong L, Chen L, Mazzola R, Caldwell J, Tang H, Allard ML, Buckle RN, Gauuan PJ, Holst CL, Martin GS, Naicker KP, Vellekoop S, Agrawal S, Liu R, Kong R, Ingravallo P, Xia E, Zhai Y, Nomeir A, Kozlowski JA.
Abstract : HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.
|
Antiviral activity against HCV genotype 3a by replicon assay
|
Hepatitis C virus subtype 3a
|
0.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of silyl proline containing HCV NS5A inhibitors with pan-genotype activity: SAR development.
Year : 2016
Volume : 26
Issue : 5
First Page : 1475
Last Page : 1479
Authors : Nair AG, Zeng Q, Selyutin O, Rosenblum SB, Jiang Y, Yang DY, Keertikar K, Zhou G, Dwyer MP, Kim SH, Shankar B, Yu W, Tong L, Chen L, Mazzola R, Caldwell J, Tang H, Allard ML, Buckle RN, Gauuan PJ, Holst CL, Martin GS, Naicker KP, Vellekoop S, Agrawal S, Liu R, Kong R, Ingravallo P, Xia E, Zhai Y, Nomeir A, Kozlowski JA.
Abstract : HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.
|
Antiviral activity against HCV genotype 1a expressing NS5A Y93H mutant by replicon assay
|
Hepatitis C virus subtype 1a
|
198.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of silyl proline containing HCV NS5A inhibitors with pan-genotype activity: SAR development.
Year : 2016
Volume : 26
Issue : 5
First Page : 1475
Last Page : 1479
Authors : Nair AG, Zeng Q, Selyutin O, Rosenblum SB, Jiang Y, Yang DY, Keertikar K, Zhou G, Dwyer MP, Kim SH, Shankar B, Yu W, Tong L, Chen L, Mazzola R, Caldwell J, Tang H, Allard ML, Buckle RN, Gauuan PJ, Holst CL, Martin GS, Naicker KP, Vellekoop S, Agrawal S, Liu R, Kong R, Ingravallo P, Xia E, Zhai Y, Nomeir A, Kozlowski JA.
Abstract : HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.
|
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
|
4.92
%
|
|
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.
|
Inhibition of NS5A in HCV genotype 1b assessed as decrease in viral replication
|
Hepatitis C virus subtype 1b
|
0.004
nM
|
|
Journal : ACS Med Chem Lett
Title : In Praise of Remarkably Powerful Centamolecular Therapeutic Agents.
Year : 2019
Volume : 10
Issue : 8
First Page : 1094
Last Page : 1097
Authors : Meanwell NA, Ewing WR.
Abstract : While biological medications have addressed many important and challenging therapeutic targets, the pharmacopeia is still dominated by centamolecules. In this Viewpoint, we illustrate the impact of centamolecule drugs on mortality and morbidity due to chronic viral infections and present select examples from other disease areas that highlight some of their remarkably powerful biochemical effects.
|
Inhibition of NS5A in HCV genotype 1b infected in human HuH7.5/Con1/SG-Neo(I)-hRluc2aUb cells assessed as inhibition of replicon levels incubated for 72 hrs by luciferase reporter gene assay
|
Hepatitis C virus subtype 1b
|
0.023
nM
|
|
Journal : J Med Chem
Title : Discovery and Characterization of Potent Pan-Genotypic HCV NS5A Inhibitors Containing Novel Tricyclic Central Core Leading to Clinical Candidate.
Year : 2019
Volume : 62
Issue : 23
First Page : 10563
Last Page : 10582
Authors : Ramdas V, Talwar R, Banerjee M, Joshi AA, Das AK, Walke DS, Borhade P, Dhayagude U, Loriya R, Gote G, Bommakanti A, Sivaram A, Agarwal G, Goswami A, Nigade P, Mehta M, Patil V, Modi D, Kumar H, Mallurwar S, Dash A, Modi F, Kuldharan S, Srivastava P, Singh M, Narasimham L, Gundu J, Sharma S, Kamboj RK, Palle VP.
Abstract : The identification of a novel class of potent pan-genotypic NS5A inhibitors with good pharmacokinetic profile suitable for potential use in treating HCV infections is disclosed here. The present series of compounds are with less complex tricyclic central core, identified through a systematic SAR study carried out on biphenyl moiety. The SAR outcome has confirmed the requirement of near planar and linear conformation of the molecule to achieve the best pan-genotypic activity. In addition, SAR with substituted imidazoles on improvement of antiviral activity is disclosed. The newly identified compounds 12, 16, 19-21 have shown desirable pharmacokinetic profiles with a favorable uptake of compounds in liver and maintained a significant concentration for up to 8 h in the liver. In addition, compounds 20 and 21 have shown superior pan-genotypic anti-HCV activity compared to ledipasvir and daclatasvir. Additional characterization and preliminary safety assessment resulted in the identification of compound 20 as a potential clinical candidate.
|
Inhibition of NS5A in HCV genotype 2a infected in human Huh7.5/J6/JFH1/EMCVIRES/hRlucNeo cells assessed as inhibition of replicon levels incubated for 72 hrs by luciferase reporter gene assay
|
Hepatitis C virus subtype 2a
|
0.009
nM
|
|
Journal : J Med Chem
Title : Discovery and Characterization of Potent Pan-Genotypic HCV NS5A Inhibitors Containing Novel Tricyclic Central Core Leading to Clinical Candidate.
Year : 2019
Volume : 62
Issue : 23
First Page : 10563
Last Page : 10582
Authors : Ramdas V, Talwar R, Banerjee M, Joshi AA, Das AK, Walke DS, Borhade P, Dhayagude U, Loriya R, Gote G, Bommakanti A, Sivaram A, Agarwal G, Goswami A, Nigade P, Mehta M, Patil V, Modi D, Kumar H, Mallurwar S, Dash A, Modi F, Kuldharan S, Srivastava P, Singh M, Narasimham L, Gundu J, Sharma S, Kamboj RK, Palle VP.
Abstract : The identification of a novel class of potent pan-genotypic NS5A inhibitors with good pharmacokinetic profile suitable for potential use in treating HCV infections is disclosed here. The present series of compounds are with less complex tricyclic central core, identified through a systematic SAR study carried out on biphenyl moiety. The SAR outcome has confirmed the requirement of near planar and linear conformation of the molecule to achieve the best pan-genotypic activity. In addition, SAR with substituted imidazoles on improvement of antiviral activity is disclosed. The newly identified compounds 12, 16, 19-21 have shown desirable pharmacokinetic profiles with a favorable uptake of compounds in liver and maintained a significant concentration for up to 8 h in the liver. In addition, compounds 20 and 21 have shown superior pan-genotypic anti-HCV activity compared to ledipasvir and daclatasvir. Additional characterization and preliminary safety assessment resulted in the identification of compound 20 as a potential clinical candidate.
|
Inhibition of NS5A in HCV genotype 1a infected in HuH-Lcu-Neo cells assessed as reduction in viral replication incubated for 48 hrs by luciferase reporter gene assay
|
Hepatitis C virus subtype 1a
|
0.0324
nM
|
|
Journal : J Med Chem
Title : GSK2818713, a Novel Biphenylene Scaffold-Based Hepatitis C NS5A Replication Complex Inhibitor with Broad Genotype Coverage.
Year : 2020
Volume : 63
Issue : 8
First Page : 4155
Last Page : 4170
Authors : Kazmierski WM, Baskaran S, Walker JT, Miriyala N, Meesala R, Beesu M, Adjabeng G, Grimes RM, Hamatake R, Leivers MR, Crosby R, Xia B, Remlinger K.
Abstract : Pan-genotype NS5A inhibitors underpin hugely successful hepatitis C virus (HCV) therapy. The discovery of GSK2818713 (13), a nonstructural protein 5A (NS5A) HCV inhibitor characterized by a significantly improved genotype coverage relative to first-generation NS5A inhibitor daclatasvir (DCV), is detailed herein. The SAR analysis revealed cooperative potency effects of the biphenylene, bicyclic pyrrolidine (Aoc), and methyl-threonine structural motifs. Relative to DCV, 13 improved activity against genotype 1a (gt1a) and gt1b NS5A variants as well as HCV chimeric replicons containing NS5A fragments from genotypes 2-6. Long-term treatment of subgenomic replicons with 13 potently and durably decreased HCV RNA levels for gt1a, gt2a, and gt3a. These properties, suitable pharmacokinetics, and the lack of cross-resistance resulted in the selection of 13 as a preclinical candidate.
|
Inhibition of NS5A in HCV genotype 1b infected in HuH-Lcu-Neo cells assessed as reduction in viral replication incubated for 48 hrs by luciferase reporter gene assay
|
Hepatitis C virus subtype 1b
|
0.0081
nM
|
|
Journal : J Med Chem
Title : GSK2818713, a Novel Biphenylene Scaffold-Based Hepatitis C NS5A Replication Complex Inhibitor with Broad Genotype Coverage.
Year : 2020
Volume : 63
Issue : 8
First Page : 4155
Last Page : 4170
Authors : Kazmierski WM, Baskaran S, Walker JT, Miriyala N, Meesala R, Beesu M, Adjabeng G, Grimes RM, Hamatake R, Leivers MR, Crosby R, Xia B, Remlinger K.
Abstract : Pan-genotype NS5A inhibitors underpin hugely successful hepatitis C virus (HCV) therapy. The discovery of GSK2818713 (13), a nonstructural protein 5A (NS5A) HCV inhibitor characterized by a significantly improved genotype coverage relative to first-generation NS5A inhibitor daclatasvir (DCV), is detailed herein. The SAR analysis revealed cooperative potency effects of the biphenylene, bicyclic pyrrolidine (Aoc), and methyl-threonine structural motifs. Relative to DCV, 13 improved activity against genotype 1a (gt1a) and gt1b NS5A variants as well as HCV chimeric replicons containing NS5A fragments from genotypes 2-6. Long-term treatment of subgenomic replicons with 13 potently and durably decreased HCV RNA levels for gt1a, gt2a, and gt3a. These properties, suitable pharmacokinetics, and the lack of cross-resistance resulted in the selection of 13 as a preclinical candidate.
|
Inhibition of NS5A in HCV genotype 2a con infected in HuH-Lcu-Neo cells assessed as reduction in viral replication incubated for 48 hrs by luciferase reporter gene assay
|
Hepatitis C virus subtype 2a
|
52.85
nM
|
|
Journal : J Med Chem
Title : GSK2818713, a Novel Biphenylene Scaffold-Based Hepatitis C NS5A Replication Complex Inhibitor with Broad Genotype Coverage.
Year : 2020
Volume : 63
Issue : 8
First Page : 4155
Last Page : 4170
Authors : Kazmierski WM, Baskaran S, Walker JT, Miriyala N, Meesala R, Beesu M, Adjabeng G, Grimes RM, Hamatake R, Leivers MR, Crosby R, Xia B, Remlinger K.
Abstract : Pan-genotype NS5A inhibitors underpin hugely successful hepatitis C virus (HCV) therapy. The discovery of GSK2818713 (13), a nonstructural protein 5A (NS5A) HCV inhibitor characterized by a significantly improved genotype coverage relative to first-generation NS5A inhibitor daclatasvir (DCV), is detailed herein. The SAR analysis revealed cooperative potency effects of the biphenylene, bicyclic pyrrolidine (Aoc), and methyl-threonine structural motifs. Relative to DCV, 13 improved activity against genotype 1a (gt1a) and gt1b NS5A variants as well as HCV chimeric replicons containing NS5A fragments from genotypes 2-6. Long-term treatment of subgenomic replicons with 13 potently and durably decreased HCV RNA levels for gt1a, gt2a, and gt3a. These properties, suitable pharmacokinetics, and the lack of cross-resistance resulted in the selection of 13 as a preclinical candidate.
|
Inhibition of NS5A in patient-derived HCV genotype 2a infected in HuH-Lcu-Neo cells assessed as reduction in viral replication incubated for 48 hrs by luciferase reporter gene assay
|
Hepatitis C virus subtype 2a
|
49.4
nM
|
|
Journal : J Med Chem
Title : GSK2818713, a Novel Biphenylene Scaffold-Based Hepatitis C NS5A Replication Complex Inhibitor with Broad Genotype Coverage.
Year : 2020
Volume : 63
Issue : 8
First Page : 4155
Last Page : 4170
Authors : Kazmierski WM, Baskaran S, Walker JT, Miriyala N, Meesala R, Beesu M, Adjabeng G, Grimes RM, Hamatake R, Leivers MR, Crosby R, Xia B, Remlinger K.
Abstract : Pan-genotype NS5A inhibitors underpin hugely successful hepatitis C virus (HCV) therapy. The discovery of GSK2818713 (13), a nonstructural protein 5A (NS5A) HCV inhibitor characterized by a significantly improved genotype coverage relative to first-generation NS5A inhibitor daclatasvir (DCV), is detailed herein. The SAR analysis revealed cooperative potency effects of the biphenylene, bicyclic pyrrolidine (Aoc), and methyl-threonine structural motifs. Relative to DCV, 13 improved activity against genotype 1a (gt1a) and gt1b NS5A variants as well as HCV chimeric replicons containing NS5A fragments from genotypes 2-6. Long-term treatment of subgenomic replicons with 13 potently and durably decreased HCV RNA levels for gt1a, gt2a, and gt3a. These properties, suitable pharmacokinetics, and the lack of cross-resistance resulted in the selection of 13 as a preclinical candidate.
|
Inhibition of NS5A in HCV genotype 3a con infected in HuH-Lcu-Neo cells assessed as reduction in viral replication incubated for 48 hrs by luciferase reporter gene assay
|
Hepatitis C virus subtype 3a
|
0.4115
nM
|
|
Journal : J Med Chem
Title : GSK2818713, a Novel Biphenylene Scaffold-Based Hepatitis C NS5A Replication Complex Inhibitor with Broad Genotype Coverage.
Year : 2020
Volume : 63
Issue : 8
First Page : 4155
Last Page : 4170
Authors : Kazmierski WM, Baskaran S, Walker JT, Miriyala N, Meesala R, Beesu M, Adjabeng G, Grimes RM, Hamatake R, Leivers MR, Crosby R, Xia B, Remlinger K.
Abstract : Pan-genotype NS5A inhibitors underpin hugely successful hepatitis C virus (HCV) therapy. The discovery of GSK2818713 (13), a nonstructural protein 5A (NS5A) HCV inhibitor characterized by a significantly improved genotype coverage relative to first-generation NS5A inhibitor daclatasvir (DCV), is detailed herein. The SAR analysis revealed cooperative potency effects of the biphenylene, bicyclic pyrrolidine (Aoc), and methyl-threonine structural motifs. Relative to DCV, 13 improved activity against genotype 1a (gt1a) and gt1b NS5A variants as well as HCV chimeric replicons containing NS5A fragments from genotypes 2-6. Long-term treatment of subgenomic replicons with 13 potently and durably decreased HCV RNA levels for gt1a, gt2a, and gt3a. These properties, suitable pharmacokinetics, and the lack of cross-resistance resulted in the selection of 13 as a preclinical candidate.
|
Inhibition of NS5A in patient-derived HCV genotype 3a infected in HuH-Lcu-Neo cells assessed as reduction in viral replication incubated for 48 hrs by luciferase reporter gene assay
|
Hepatitis C virus subtype 3a
|
0.1145
nM
|
|
Journal : J Med Chem
Title : GSK2818713, a Novel Biphenylene Scaffold-Based Hepatitis C NS5A Replication Complex Inhibitor with Broad Genotype Coverage.
Year : 2020
Volume : 63
Issue : 8
First Page : 4155
Last Page : 4170
Authors : Kazmierski WM, Baskaran S, Walker JT, Miriyala N, Meesala R, Beesu M, Adjabeng G, Grimes RM, Hamatake R, Leivers MR, Crosby R, Xia B, Remlinger K.
Abstract : Pan-genotype NS5A inhibitors underpin hugely successful hepatitis C virus (HCV) therapy. The discovery of GSK2818713 (13), a nonstructural protein 5A (NS5A) HCV inhibitor characterized by a significantly improved genotype coverage relative to first-generation NS5A inhibitor daclatasvir (DCV), is detailed herein. The SAR analysis revealed cooperative potency effects of the biphenylene, bicyclic pyrrolidine (Aoc), and methyl-threonine structural motifs. Relative to DCV, 13 improved activity against genotype 1a (gt1a) and gt1b NS5A variants as well as HCV chimeric replicons containing NS5A fragments from genotypes 2-6. Long-term treatment of subgenomic replicons with 13 potently and durably decreased HCV RNA levels for gt1a, gt2a, and gt3a. These properties, suitable pharmacokinetics, and the lack of cross-resistance resulted in the selection of 13 as a preclinical candidate.
|
Inhibition of HCV genotype 1b NS5A
|
Hepatitis C virus subtype 1b
|
0.002
nM
|
|
Journal : MedChemComm
Title : Scaffold hybridization strategy towards potent hydroxamate-based inhibitors of <i>Flaviviridae</i> viruses and <i>Trypanosoma</i> species.
Year : 2019
Volume : 10
Issue : 6
First Page : 991
Last Page : 1006
Authors : Giannakopoulou E, Pardali V, Frakolaki E, Siozos V, Myrianthopoulos V, Mikros E, Taylor MC, Kelly JM, Vassilaki N, Zoidis G.
Abstract : Infections with <i>Flaviviridae</i> viruses, such as hepatitis C virus (HCV) and dengue virus (DENV) pose global health threats. Infected individuals are at risk of developing chronic liver failure or haemorrhagic fever respectively, often with a fatal outcome if left untreated. Diseases caused by tropical parasites of the <i>Trypanosoma</i> species, <i>T. brucei</i> and <i>T. cruzi</i>, constitute significant socioeconomic burden in sub-Saharan Africa and continental Latin America, yet drug development is under-funded. Anti-HCV chemotherapy is associated with severe side effects and high cost, while dengue has no clinically approved therapy and antiparasitic drugs are outdated and difficult to administer. Moreover, drug resistance is an emerging concern. Consequently, the need for new revolutionary chemotherapies is urgent. By utilizing a molecular framework combination approach, we combined two distinct chemical entities with proven antiviral and trypanocidal activity into a novel hybrid scaffold attached by an acetohydroxamic acid group (CH<sub>2</sub>CONHOH), aiming at derivatives with dual activity. The novel spiro-carbocyclic substituted hydantoin analogues were rationally designed, synthesized and evaluated for their potency against three HCV genotypes (1b, 3a, 4a), DENV and two <i>Trypanosoma</i> species (<i>T. brucei</i>, <i>T. cruzi</i>). They exhibited significant EC<sub>50</sub> values and remarkable selectivity indices. Several modifications were undertaken to further explore the structure activity relationships (SARs) and confirm the pivotal role of the acetohydroxamic acid metal binding group.
|
Inhibition of NS5A in HCV genotype 1b infected in human HuH7 replicon cells assessed as reduction in subgenomic viral RNA replication treated for 2 days followed by compound washout and subsequent compound dosing measured after 1 day by SEAP reporter gene assay
|
Hepatitis C virus subtype 1b
|
0.009
nM
|
|
Journal : Eur J Med Chem
Title : A novel, potent, and orally bioavailable thiazole HCV NS5A inhibitor for the treatment of hepatitis C virus.
Year : 2019
Volume : 167
First Page : 245
Last Page : 268
Authors : Yeh TK, Kang IJ, Hsu TA, Lee YC, Lee CC, Hsu SJ, Tian YW, Yang HY, Chen CT, Chao YS, Yueh A, Chern JH.
Abstract : A medicinal chemistry program based on the small-molecule HCV NS5A inhibitor daclatasvir has led to the discovery of dimeric phenylthiazole compound 8, a novel and potent HCV NS5A inhibitor. The subsequent SAR studies and optimization revealed that the cycloalkyl amide derivatives 27a-29a exhibited superior potency against GT1b with GT1b EC<sub>50</sub> values at picomolar concentration. Interestingly, high diastereospecificity for HCV inhibition was observed in this class with the (1R,2S,1'R,2'S) diastereomer displaying the highest GT1b inhibitory activity. The best inhibitor 27a was found to be 3-fold more potent (GT1b EC<sub>50</sub> = 0.003 nM) than daclatasvir (GT1b EC<sub>50</sub> = 0.009 nM) against GT1b, and no detectable in vitro cytotoxicity was observed (CC<sub>50</sub> > 50 μM). Pharmacokinetic studies demonstrated that compound 27a had an excellent pharmacokinetic profiles with a superior oral exposure and desired bioavailability after oral administration in both rats and dogs, and therefore it was selected as a developmental candidate for the treatment of HCV infection.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
100.4
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-222.71
%
|
|
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
|
5.77
%
|
|
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
|
4.73
%
|
|
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
|
5.77
%
|
|
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
|
4.73
%
|
|
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
|
Hepatitis C virus
|
99.0
%
|
|
Journal : Eur J Med Chem
Title : Hepatitis C - New drugs and treatment prospects.
Year : 2019
Volume : 165
First Page : 225
Last Page : 249
Authors : Zając M, Muszalska I, Sobczak A, Dadej A, Tomczak S, Jelińska A.
Abstract : Hepatitis C virus (HCV) affects approx. 3% of the world's population and accounts for ca 300 000 deaths per year. 80% of individuals with HCV develop chronic symptoms which, when untreated, may cause cirrhosis (27%) or hepatocellular carcinoma (25%). The hepatitis C virus is a (+)ssRNA enveloped virus of the family Flaviviridae. Seven major HCV genotypes and their subtypes (a, b) have been identified. In the 1990s, interferons alpha-2 were used in the treatment of HCV and in the next decade HCV therapy was based on pegylated interferon alpha-2 in combination with ribavirin. Since 2011, interferons alpha, DNA and RNA polymerase inhibitors, NS3/4A RNA protease inhibitors, NS5 RNA serine protease inhibitors, NS5B RNA polymerase inhibitors have been approved for clinical use. Monotherapy is avoided in medication due to rapidly developing viral resistance. A total of 113 papers were included comprising original publications and reviews. The paper reviews the molecular targets and chemical structures of drugs used in HCV treatment. Indications and contraindications for anti-HCV drugs are also discussed together with application regimens.
|
Inhibition of NS5A in Hepatitis C virus subtype 1a replicon assessed as reduction in viral replication using Ac-Asp-Glu-Asp (EDANS)-Glu-Glu-Abu-(COO) Ala-Ser-Lys (DABCYL)-NH2 as substrate measured after 72 hrs by FRET assay
|
Hepatitis C virus subtype 1a
|
0.05
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of a novel unsymmetrical structural class of HCV NS5A inhibitors with low picomolar antiviral activity.
Year : 2020
Volume : 30
Issue : 5
First Page : 126932
Last Page : 126932
Authors : Nakamura H, Akagi Y, Terui T, Fujioka S, Komoda Y, Kinoshita W, Maeda K, Ukaji Y, Inaba T.
Abstract : A novel unsymmetrical structural class of HCV NS5A inhibitors showing picomolar range antiviral activity has been identified. An unsymmetrical lead compound 2, generated from a substructure of a known symmetrical inhibitor 1, was optimized by extension of its substituents to interact with the hitherto unexplored site of the target protein. This approach afforded novel highly potent unsymmetrical inhibitor 20, which not only equally inhibited HCV genotypes1a, 1b, and 2a with EC<sub>50</sub> values in the picomolar range, but also inhibited the 1a Q30K mutant induced by a launched symmetrical inhibitor daclatasvir with an EC<sub>50</sub> in the low nanomolar range.
|
Inhibition of NS5A in Hepatitis C virus subtype 1b replicon assessed as reduction in viral replication using Ac-Asp-Glu-Asp (EDANS)-Glu-Glu-Abu-(COO) Ala-Ser-Lys (DABCYL)-NH2 as substrate measured after 72 hrs by FRET assay
|
Hepatitis C virus subtype 1b
|
0.009
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of a novel unsymmetrical structural class of HCV NS5A inhibitors with low picomolar antiviral activity.
Year : 2020
Volume : 30
Issue : 5
First Page : 126932
Last Page : 126932
Authors : Nakamura H, Akagi Y, Terui T, Fujioka S, Komoda Y, Kinoshita W, Maeda K, Ukaji Y, Inaba T.
Abstract : A novel unsymmetrical structural class of HCV NS5A inhibitors showing picomolar range antiviral activity has been identified. An unsymmetrical lead compound 2, generated from a substructure of a known symmetrical inhibitor 1, was optimized by extension of its substituents to interact with the hitherto unexplored site of the target protein. This approach afforded novel highly potent unsymmetrical inhibitor 20, which not only equally inhibited HCV genotypes1a, 1b, and 2a with EC<sub>50</sub> values in the picomolar range, but also inhibited the 1a Q30K mutant induced by a launched symmetrical inhibitor daclatasvir with an EC<sub>50</sub> in the low nanomolar range.
|
Inhibition of NS5A in Hepatitis C virus subtype 2a replicon assessed as reduction in viral replication using Ac-Asp-Glu-Asp (EDANS)-Glu-Glu-Abu-(COO) Ala-Ser-Lys (DABCYL)-NH2 as substrate measured after 72 hrs by FRET assay
|
Hepatitis C virus subtype 2a
|
0.071
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of a novel unsymmetrical structural class of HCV NS5A inhibitors with low picomolar antiviral activity.
Year : 2020
Volume : 30
Issue : 5
First Page : 126932
Last Page : 126932
Authors : Nakamura H, Akagi Y, Terui T, Fujioka S, Komoda Y, Kinoshita W, Maeda K, Ukaji Y, Inaba T.
Abstract : A novel unsymmetrical structural class of HCV NS5A inhibitors showing picomolar range antiviral activity has been identified. An unsymmetrical lead compound 2, generated from a substructure of a known symmetrical inhibitor 1, was optimized by extension of its substituents to interact with the hitherto unexplored site of the target protein. This approach afforded novel highly potent unsymmetrical inhibitor 20, which not only equally inhibited HCV genotypes1a, 1b, and 2a with EC<sub>50</sub> values in the picomolar range, but also inhibited the 1a Q30K mutant induced by a launched symmetrical inhibitor daclatasvir with an EC<sub>50</sub> in the low nanomolar range.
|
Antiviral activity against wild-type HCV J6/JFH/JC1 infected in human Huh7.5 cells assessed as inhibition of viral replication measured after 72 hrs by qRT-PCR analysis
|
Hepatitis C virus
|
0.01767
nM
|
|
Journal : J Med Chem
Title : Design and Synthesis of Cajanine Analogues against Hepatitis C Virus through Down-Regulating Host Chondroitin Sulfate N-Acetylgalactosaminyltransferase 1.
Year : 2016
Volume : 59
Issue : 22.0
First Page : 10268
Last Page : 10284
Authors : Ji XY,Chen JH,Zheng GH,Huang MH,Zhang L,Yi H,Jin J,Jiang JD,Peng ZG,Li ZR
Abstract : There still remains a need to develop new anti-HCV agents with distinct mechanism of action (MOA) due to the occurrence of resistance to direct-acting antiviral agents (DAAs). Cajanine, a stilbenic component isolated from Cajanus cajan L., was identified as a potent HCV inhibitor by phenotypic screening in this work (EC = 3.17 ± 0.75 μM). The intensive structure optimization provided significant insights into the structure-activity relationships. Furthermore, the MOA study revealed that cajanine inhibited HCV replications via down-regulating a cellular protein chondroitin sulfate N-acetylgalactosaminyltransferase 1. In consistency with this host-targeting mechanism, cajanine showed the similar magnitude of inhibitory activity against both drug-resistant and wild-type HCV and synergistically inhibited HCV replication with approved DAAs. Taken together, our study not only presented cajanine derivatives as a novel class of anti-HCV agents but also discovered a promising anti-HCV target to combat drug resistance.
|
Inhibition of Hepatitis C virus 2a NS5A
|
Hepatitis C virus subtype 2a
|
0.071
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Orally bioavailable HCV NS5A inhibitors of unsymmetrical structural class.
Year : 2020
Volume : 30
Issue : 17
First Page : 127361
Last Page : 127361
Authors : Nakamura H,Fujioka S,Terui T,Okuda S,Kondo K,Tamatani Y,Akagi Y,Komoda Y,Kinoshita W,Ito S,Maeda K,Ukaji Y,Inaba T
Abstract : A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC values in the low nanomolar range.
|
Inhibition of Hepatitis C virus 3a NS5A
|
Hepatitis C virus subtype 3a
|
0.146
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Orally bioavailable HCV NS5A inhibitors of unsymmetrical structural class.
Year : 2020
Volume : 30
Issue : 17
First Page : 127361
Last Page : 127361
Authors : Nakamura H,Fujioka S,Terui T,Okuda S,Kondo K,Tamatani Y,Akagi Y,Komoda Y,Kinoshita W,Ito S,Maeda K,Ukaji Y,Inaba T
Abstract : A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC values in the low nanomolar range.
|
Inhibition of Hepatitis C virus 1a NS5A Q30R mutant
|
Hepatitis C virus subtype 1a
|
61.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Orally bioavailable HCV NS5A inhibitors of unsymmetrical structural class.
Year : 2020
Volume : 30
Issue : 17
First Page : 127361
Last Page : 127361
Authors : Nakamura H,Fujioka S,Terui T,Okuda S,Kondo K,Tamatani Y,Akagi Y,Komoda Y,Kinoshita W,Ito S,Maeda K,Ukaji Y,Inaba T
Abstract : A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC values in the low nanomolar range.
|
Inhibition of Hepatitis C virus 1a H77 NS5A
|
Hepatitis C virus subtype 1a
|
0.05
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Orally bioavailable HCV NS5A inhibitors of unsymmetrical structural class.
Year : 2020
Volume : 30
Issue : 17
First Page : 127361
Last Page : 127361
Authors : Nakamura H,Fujioka S,Terui T,Okuda S,Kondo K,Tamatani Y,Akagi Y,Komoda Y,Kinoshita W,Ito S,Maeda K,Ukaji Y,Inaba T
Abstract : A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC values in the low nanomolar range.
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Inhibition of Hepatitis C virus 1b con1 NS5A
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Hepatitis C virus subtype 1b
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0.009
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Orally bioavailable HCV NS5A inhibitors of unsymmetrical structural class.
Year : 2020
Volume : 30
Issue : 17
First Page : 127361
Last Page : 127361
Authors : Nakamura H,Fujioka S,Terui T,Okuda S,Kondo K,Tamatani Y,Akagi Y,Komoda Y,Kinoshita W,Ito S,Maeda K,Ukaji Y,Inaba T
Abstract : A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC values in the low nanomolar range.
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Antiviral activity against HCV infected in human Huh-7 cells assessed as reduction in viral replication measured after 48 hrs by luciferase reporter gene assay
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Hepatitis C virus
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0.031
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and evaluation of liver-specific gemcitabine prodrugs for potential treatment of hepatitis C virus infection and hepatocellular carcinoma.
Year : 2021
Volume : 213
First Page : 113135
Last Page : 113135
Authors : Stephenson AA,Cao S,Taggart DJ,Vyavahare VP,Suo Z
Abstract : Many successful anti-viral and anti-cancer drugs are nucleoside analogs, which disrupt RNA and/or DNA synthesis. Here, we present liver-specific prodrugs of the chemotherapy drug gemcitabine (2',2'-difluorodeoxycytidine) for the treatment of hepatitis C virus (HCV) infection and hepatocellular carcinoma. The prodrugs were synthesized by introducing aromatic functional moieties to the cytosine 4-NH group of gemcitabine via amide bonds. The chemical modification was designed to i) enable passive diffusion across cellular membrane, ii) protect the prodrugs from inactivating deamination by cellular enzymes, and iii) allow release of active gemcitabine after amide hydrolysis by high levels of carboxylesterases in the liver. We found that many of our prodrugs exhibited similar toxicity as gemcitabine toward liver- and kidney-derived cancer cell lines but were 24- to 620-fold less cytotoxic than gemcitabine in breast- and pancreas-derived cancer cells, respectively. The prodrugs also inhibited an HCV replicon with IC values ranging from 10 nM-1.7 μM. Moreover, many of the prodrugs had therapeutic index values of >10,000 and have synergetic effects when combined with other Food and Drug Administration-approved anti-HCV small molecule drugs. These characteristics support the development of gemcitabine prodrugs as liver-specific therapeutics.
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Inhibition of HCV genotype 1b NS5A infected in HuH-7-Luc/Neo-ET cells assessed as reduction in viral replication measured by Luciferase reporter gene assay
|
Hepatitis C virus subtype 1b
|
0.032
nM
|
|
|
Inhibition of HCV genotype 1a NS5A infected in HuH-7-Luc/Neo-ET cells assessed as reduction in viral replication measured by Luciferase reporter gene assay
|
Hepatitis C virus subtype 1a
|
0.079
nM
|
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