|
Inhibition of hepatitis C virus in a cell based HCV replicon assay.
|
Hepatitis C virus
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity study on a novel series of macrocyclic inhibitors of the hepatitis C virus NS3 protease leading to the discovery of BILN 2061.
Year : 2004
Volume : 47
Issue : 7
First Page : 1605
Last Page : 1608
Authors : Llinàs-Brunet M, Bailey MD, Bolger G, Brochu C, Faucher AM, Ferland JM, Garneau M, Ghiro E, Gorys V, Grand-Maître C, Halmos T, Lapeyre-Paquette N, Liard F, Poirier M, Rhéaume M, Tsantrizos YS, Lamarre D.
Abstract : From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.
|
Inhibitory concentration against hepatitis C virus NS3 protease
|
Hepatitis C virus
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity study on a novel series of macrocyclic inhibitors of the hepatitis C virus NS3 protease leading to the discovery of BILN 2061.
Year : 2004
Volume : 47
Issue : 7
First Page : 1605
Last Page : 1608
Authors : Llinàs-Brunet M, Bailey MD, Bolger G, Brochu C, Faucher AM, Ferland JM, Garneau M, Ghiro E, Gorys V, Grand-Maître C, Halmos T, Lapeyre-Paquette N, Liard F, Poirier M, Rhéaume M, Tsantrizos YS, Lamarre D.
Abstract : From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.
|
Inhibition of HCV 1b NS3 protease
|
Hepatitis C virus subtype 1b
|
0.66
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Phenylglycine as a novel P2 scaffold in hepatitis C virus NS3 protease inhibitors.
Year : 2007
Volume : 15
Issue : 3
First Page : 1448
Last Page : 1474
Authors : Ortqvist P, Peterson SD, Kerblom E, Gossas T, Sabnis YA, Fransson R, Lindeberg G, Helena Danielson U, Karlén A, Sandström A.
Abstract : Molecular modeling and inhibitory potencies of tetrapeptide protease inhibitors of HCV NS3 proposed phenylglycine as a new promising P2 residue. The results suggest that phenylglycine might be capable of interacting with the NS3 (protease-helicase/NTPase) in ways not possible for the common P2 proline-based inhibitors. Thus, a series of tripeptides, both linear and macrocyclic, based on p-hydroxy-phenylglycine in the P2 position were prepared and their inhibitory effect determined. When the p-hydroxy group was replaced by methoxy, isoquinolin-, or quinolinyloxy functions, inhibitors with improved potencies were obtained. The P2 phenylglycine-based inhibitors were further optimized by C-terminal extension to acyl sulfonamides and by P1-P3 cyclization, which gave products with inhibition constants in the nanomolar range ( approximately 75nM).
|
Inhibition of HCV 1a NS3 protease
|
Hepatitis C virus subtype 1a
|
0.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Phenylglycine as a novel P2 scaffold in hepatitis C virus NS3 protease inhibitors.
Year : 2007
Volume : 15
Issue : 3
First Page : 1448
Last Page : 1474
Authors : Ortqvist P, Peterson SD, Kerblom E, Gossas T, Sabnis YA, Fransson R, Lindeberg G, Helena Danielson U, Karlén A, Sandström A.
Abstract : Molecular modeling and inhibitory potencies of tetrapeptide protease inhibitors of HCV NS3 proposed phenylglycine as a new promising P2 residue. The results suggest that phenylglycine might be capable of interacting with the NS3 (protease-helicase/NTPase) in ways not possible for the common P2 proline-based inhibitors. Thus, a series of tripeptides, both linear and macrocyclic, based on p-hydroxy-phenylglycine in the P2 position were prepared and their inhibitory effect determined. When the p-hydroxy group was replaced by methoxy, isoquinolin-, or quinolinyloxy functions, inhibitors with improved potencies were obtained. The P2 phenylglycine-based inhibitors were further optimized by C-terminal extension to acyl sulfonamides and by P1-P3 cyclization, which gave products with inhibition constants in the nanomolar range ( approximately 75nM).
|
Antiviral activity against HCV 1b-N
|
Hepatitis C virus subtype 1b
|
4.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Evolution of resistant M414T mutants among hepatitis C virus replicon cells treated with polymerase inhibitor A-782759.
Year : 2007
Volume : 51
Issue : 6
First Page : 1889
Last Page : 1896
Authors : Lu L, Mo H, Pilot-Matias TJ, Molla A.
Abstract : Treatment of hepatitis C virus (HCV) replicon cells with any single specific anti-HCV inhibitor in vitro leads to a rapid selection of resistant mutants. However, the source and the kinetic evolution of these resistant mutants during treatment are poorly understood. In this study we developed allele-specific real-time PCR assays for quantitative detection of the M414T mutant that was selected by a number of benzothiadiazine HCV polymerase inhibitors. Low levels of preexisting M414T mutants were detected in both 1b-con1 (0.22%) and 1b-N (0.18%) subgenomic replicon cell lines, as well as in 6 of 15 HCV RNA isolated from the sera of treatment-naive HCV-infected patients ranging from 0.11 to 0.60%. The proportion of M414T mutants in replicons rapidly increased in a dose-dependent manner upon treatment with benzothiadiazine inhibitor A-782759. After 4 days of treatment, 2.5, 26, or 60% of the replicon population contained M414T mutants with the use of A-782759 at 1x, 10x, or 100x its 50% effective concentration, respectively. In addition, the short 4-day treatment resulted in significant changes in inhibitor susceptibility in the replicon cells. Our results indicated that the resistant mutant preexisted as a minor population in replicon cells and that the mutant was selected within days of treatment with the inhibitor. The findings from this study suggested that early application of combination therapy of an HCV-specific inhibitor with interferon-based regimens or other classes of available inhibitors will be necessary to avoid quick viral rebound or treatment failure.
|
Inhibition of HCV NS3 protease by FRET assay
|
Hepatitis C virus
|
0.66
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Hepatitis C virus NS3 protease inhibitors comprising a novel aromatic P1 moiety.
Year : 2008
Volume : 16
Issue : 6
First Page : 2955
Last Page : 2967
Authors : Rönn R, Lampa A, Peterson SD, Gossas T, Akerblom E, Danielson UH, Karlén A, Sandström A.
Abstract : Inhibition of the hepatitis C virus (HCV) NS3 protease has emerged as an attractive approach to defeat the global hepatitis C epidemic. In this work, we present the synthesis and biochemical evaluation of HCV NS3 protease inhibitors comprising a non-natural aromatic P(1) moiety. A series of inhibitors with aminobenzoyl sulfonamides displaying submicromolar potencies in the full-length NS3 protease assay was prepared through a microwave-irradiated, palladium-catalyzed, amidocarbonylation protocol.
|
Antiviral activity against Hepatitis C virus infected human hepatoma cells by replicon assay
|
Hepatitis C virus
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Hepatitis C virus NS3 protease inhibitors comprising a novel aromatic P1 moiety.
Year : 2008
Volume : 16
Issue : 6
First Page : 2955
Last Page : 2967
Authors : Rönn R, Lampa A, Peterson SD, Gossas T, Akerblom E, Danielson UH, Karlén A, Sandström A.
Abstract : Inhibition of the hepatitis C virus (HCV) NS3 protease has emerged as an attractive approach to defeat the global hepatitis C epidemic. In this work, we present the synthesis and biochemical evaluation of HCV NS3 protease inhibitors comprising a non-natural aromatic P(1) moiety. A series of inhibitors with aminobenzoyl sulfonamides displaying submicromolar potencies in the full-length NS3 protease assay was prepared through a microwave-irradiated, palladium-catalyzed, amidocarbonylation protocol.
|
Inhibition of HCV NS3-4A protease
|
Hepatitis C virus
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, antiviral activity, and conformational studies of a P3 aza-peptide analog of a potent macrocyclic tripeptide HCV protease inhibitor.
Year : 2008
Volume : 18
Issue : 8
First Page : 2745
Last Page : 2750
Authors : Randolph JT, Zhang X, Huang PP, Klein LL, Kurtz KA, Konstantinidis AK, He W, Kati WM, Kempf DJ.
Abstract : BILN 2061 is a macrocyclic tripeptide inhibitor of hepatitis C virus NS3-4A protease that has shown efficacy in the clinic for treating patients infected with HCV. We have synthesized a P3 aza-peptide analog of a potent macrocyclic tripeptide inhibitor closely related to BILN 2061. This aza-derivative was found to be >2 orders of magnitude less active than the parent macrocycle in both isolated enzyme (HCV NS3-4A) and HCV subgenomic replicon assays. NMR studies of P3 aza-peptides revealed these compounds adopt a beta-turn conformation stabilized by an intramolecular H-bonding interaction. Molecular models of these structures indicate a D-like configuration of the P3 aza-residue. Thus, the configurationally undefined nature at P3 in the aza-peptide allows the compound to adopt an H-bond stabilized conformation that is substantially different from that necessary for tight binding to the active site of HCV NS3 protease.
|
Antiviral activity against HCV replicon
|
Hepatitis C virus
|
1.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, antiviral activity, and conformational studies of a P3 aza-peptide analog of a potent macrocyclic tripeptide HCV protease inhibitor.
Year : 2008
Volume : 18
Issue : 8
First Page : 2745
Last Page : 2750
Authors : Randolph JT, Zhang X, Huang PP, Klein LL, Kurtz KA, Konstantinidis AK, He W, Kati WM, Kempf DJ.
Abstract : BILN 2061 is a macrocyclic tripeptide inhibitor of hepatitis C virus NS3-4A protease that has shown efficacy in the clinic for treating patients infected with HCV. We have synthesized a P3 aza-peptide analog of a potent macrocyclic tripeptide inhibitor closely related to BILN 2061. This aza-derivative was found to be >2 orders of magnitude less active than the parent macrocycle in both isolated enzyme (HCV NS3-4A) and HCV subgenomic replicon assays. NMR studies of P3 aza-peptides revealed these compounds adopt a beta-turn conformation stabilized by an intramolecular H-bonding interaction. Molecular models of these structures indicate a D-like configuration of the P3 aza-residue. Thus, the configurationally undefined nature at P3 in the aza-peptide allows the compound to adopt an H-bond stabilized conformation that is substantially different from that necessary for tight binding to the active site of HCV NS3 protease.
|
Inhibition of full length HCV NS3/4A protease
|
Hepatitis C virus
|
0.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel potent and selective dipeptide hepatitis C virus NS3/4A serine protease inhibitors.
Year : 2008
Volume : 18
Issue : 18
First Page : 5095
Last Page : 5100
Authors : Raboisson P, Lin TI, Kock Hd, Vendeville S, Vreken WV, McGowan D, Tahri A, Hu L, Lenz O, Delouvroy F, Surleraux D, Wigerinck P, Nilsson M, Rosenquist S, Samuelsson B, Simmen K.
Abstract : Starting from the previously reported HCV NS3/4A protease inhibitor BILN 2061, we have used a fast-follower approach to identify a novel series of HCV NS3/4A protease inhibitors in which (i) the P3 amino moiety and its capping group have been truncated, (ii) a sulfonamide is introduced in the P1 cyclopropyl amino acid, (iii) the position 8 of the quinoline is substituted with a methyl or halo group, and (iv) the ring size of the macrocycle has been reduced to 14 atoms. SAR analysis performed with a limited set of compounds led to the identification of N-{17-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo [13.3.0.0 [Bartenschlager, R.; Lohmann, V. J. Gen. Virol. 2000, 81, 1631; Vincent Soriano, Antonio Madejon, Eugenia Vispo, Pablo Labarga, Javier Garcia-Samaniego, Luz Martin-Carbonero, Julie Sheldon, Marcelle Bottecchia, Paula Tuma, Pablo Barreiro Expert Opin. Emerg. Drugs, 2008, 13, 1-19]]octadec-7-ene-4-carbonyl}(1-methylcyclopropyl)(1-methylcyclopropyl)sulfonamide 19l an extremely potent (K(i)=0.20 nM, EC(50)=3.7 nM), selective, and orally bioavailable dipeptide NS3/4A protease inhibitor, which has features attractive for further preclinical development.
|
Inhibition of HCV replication in human HuH7-Rep cells containing subgenomic bicistronic clone
|
Hepatitis C virus
|
1.63
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel potent and selective dipeptide hepatitis C virus NS3/4A serine protease inhibitors.
Year : 2008
Volume : 18
Issue : 18
First Page : 5095
Last Page : 5100
Authors : Raboisson P, Lin TI, Kock Hd, Vendeville S, Vreken WV, McGowan D, Tahri A, Hu L, Lenz O, Delouvroy F, Surleraux D, Wigerinck P, Nilsson M, Rosenquist S, Samuelsson B, Simmen K.
Abstract : Starting from the previously reported HCV NS3/4A protease inhibitor BILN 2061, we have used a fast-follower approach to identify a novel series of HCV NS3/4A protease inhibitors in which (i) the P3 amino moiety and its capping group have been truncated, (ii) a sulfonamide is introduced in the P1 cyclopropyl amino acid, (iii) the position 8 of the quinoline is substituted with a methyl or halo group, and (iv) the ring size of the macrocycle has been reduced to 14 atoms. SAR analysis performed with a limited set of compounds led to the identification of N-{17-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo [13.3.0.0 [Bartenschlager, R.; Lohmann, V. J. Gen. Virol. 2000, 81, 1631; Vincent Soriano, Antonio Madejon, Eugenia Vispo, Pablo Labarga, Javier Garcia-Samaniego, Luz Martin-Carbonero, Julie Sheldon, Marcelle Bottecchia, Paula Tuma, Pablo Barreiro Expert Opin. Emerg. Drugs, 2008, 13, 1-19]]octadec-7-ene-4-carbonyl}(1-methylcyclopropyl)(1-methylcyclopropyl)sulfonamide 19l an extremely potent (K(i)=0.20 nM, EC(50)=3.7 nM), selective, and orally bioavailable dipeptide NS3/4A protease inhibitor, which has features attractive for further preclinical development.
|
Antiviral activity against HCV 1a containing chimeric genotype 1a-H77/1b-con1 subgenom in human Huh7 cells assessed as reduction in viral RNA after 7 days by RT-PCR
|
Hepatitis C virus subtype 1a
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibitors of hepatitis C virus polymerase: synthesis and biological characterization of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines.
Year : 2009
Volume : 52
Issue : 6
First Page : 1659
Last Page : 1669
Authors : Wagner R, Larson DP, Beno DW, Bosse TD, Darbyshire JF, Gao Y, Gates BD, He W, Henry RF, Hernandez LE, Hutchinson DK, Jiang WW, Kati WM, Klein LL, Koev G, Kohlbrenner W, Krueger AC, Liu J, Liu Y, Long MA, Maring CJ, Masse SV, Middleton T, Montgomery DA, Pratt JK, Stuart P, Molla A, Kempf DJ.
Abstract : The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and has been a prime target for drug discovery research. Our efforts directed toward the discovery of HCV polymerase inhibitors resulted in the identification of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines 2 and 3. The most active compound displayed activity in genotypes 1a and 1b polymerase and replicon cell culture inhibition assays at subnanomolar and low nanomolar concentrations, respectively. It also displayed an excellent pharmacokinetic profile in rats, with a plasma elimination half-life after intravenous dosing of 4.5 h, oral bioavailability of 77%, and a peak liver concentration of 21.8 microg/mL.
|
Antiviral activity against HCV isolate Con1 in human Huh7 cells assessed as reduction in viral RNA after 7 days by RT-PCR
|
Hepatitis C virus (isolate Con1)
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibitors of hepatitis C virus polymerase: synthesis and biological characterization of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines.
Year : 2009
Volume : 52
Issue : 6
First Page : 1659
Last Page : 1669
Authors : Wagner R, Larson DP, Beno DW, Bosse TD, Darbyshire JF, Gao Y, Gates BD, He W, Henry RF, Hernandez LE, Hutchinson DK, Jiang WW, Kati WM, Klein LL, Koev G, Kohlbrenner W, Krueger AC, Liu J, Liu Y, Long MA, Maring CJ, Masse SV, Middleton T, Montgomery DA, Pratt JK, Stuart P, Molla A, Kempf DJ.
Abstract : The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and has been a prime target for drug discovery research. Our efforts directed toward the discovery of HCV polymerase inhibitors resulted in the identification of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines 2 and 3. The most active compound displayed activity in genotypes 1a and 1b polymerase and replicon cell culture inhibition assays at subnanomolar and low nanomolar concentrations, respectively. It also displayed an excellent pharmacokinetic profile in rats, with a plasma elimination half-life after intravenous dosing of 4.5 h, oral bioavailability of 77%, and a peak liver concentration of 21.8 microg/mL.
|
Antiviral activity against wild type HCV 1b strain N infected in chimpanzee
|
Hepatitis C virus subtype 1b
|
1.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model.
Year : 2007
Volume : 51
Issue : 12
First Page : 4290
Last Page : 4296
Authors : Chen CM, He Y, Lu L, Lim HB, Tripathi RL, Middleton T, Hernandez LE, Beno DW, Long MA, Kati WM, Bosse TD, Larson DP, Wagner R, Lanford RE, Kohlbrenner WE, Kempf DJ, Pilot-Matias TJ, Molla A.
Abstract : A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.
|
Antiviral activity against HCV 1b strain N with NS5B polymerase C316Y mutation infected in chimpanzee measured on day 2
|
Hepatitis C virus subtype 1b
|
1.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model.
Year : 2007
Volume : 51
Issue : 12
First Page : 4290
Last Page : 4296
Authors : Chen CM, He Y, Lu L, Lim HB, Tripathi RL, Middleton T, Hernandez LE, Beno DW, Long MA, Kati WM, Bosse TD, Larson DP, Wagner R, Lanford RE, Kohlbrenner WE, Kempf DJ, Pilot-Matias TJ, Molla A.
Abstract : A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.
|
Antiviral activity against HCV 1b strain N with NS5B polymerase C316Y mutation infected in chimpanzee measured on day 5
|
Hepatitis C virus subtype 1b
|
1.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model.
Year : 2007
Volume : 51
Issue : 12
First Page : 4290
Last Page : 4296
Authors : Chen CM, He Y, Lu L, Lim HB, Tripathi RL, Middleton T, Hernandez LE, Beno DW, Long MA, Kati WM, Bosse TD, Larson DP, Wagner R, Lanford RE, Kohlbrenner WE, Kempf DJ, Pilot-Matias TJ, Molla A.
Abstract : A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.
|
Antiviral activity against HCV 1b strain N with NS5B polymerase C316Y mutation infected in chimpanzee measured on day 11
|
Hepatitis C virus subtype 1b
|
1.1
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model.
Year : 2007
Volume : 51
Issue : 12
First Page : 4290
Last Page : 4296
Authors : Chen CM, He Y, Lu L, Lim HB, Tripathi RL, Middleton T, Hernandez LE, Beno DW, Long MA, Kati WM, Bosse TD, Larson DP, Wagner R, Lanford RE, Kohlbrenner WE, Kempf DJ, Pilot-Matias TJ, Molla A.
Abstract : A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.
|
Antiviral activity against HCV 1b strain N with NS5B polymerase C316Y mutation infected in chimpanzee measured on day 28
|
Hepatitis C virus subtype 1b
|
1.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model.
Year : 2007
Volume : 51
Issue : 12
First Page : 4290
Last Page : 4296
Authors : Chen CM, He Y, Lu L, Lim HB, Tripathi RL, Middleton T, Hernandez LE, Beno DW, Long MA, Kati WM, Bosse TD, Larson DP, Wagner R, Lanford RE, Kohlbrenner WE, Kempf DJ, Pilot-Matias TJ, Molla A.
Abstract : A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.
|
Antiviral activity against HCV 1a H77 with NS5B polymerase G554D mutation infected in chimpanzee measured on day 2
|
Hepatitis C virus (isolate H77)
|
2.7
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model.
Year : 2007
Volume : 51
Issue : 12
First Page : 4290
Last Page : 4296
Authors : Chen CM, He Y, Lu L, Lim HB, Tripathi RL, Middleton T, Hernandez LE, Beno DW, Long MA, Kati WM, Bosse TD, Larson DP, Wagner R, Lanford RE, Kohlbrenner WE, Kempf DJ, Pilot-Matias TJ, Molla A.
Abstract : A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.
|
Antiviral activity against HCV 1a H77 with NS5B polymerase G554D mutation infected in chimpanzee measured on day 5
|
Hepatitis C virus (isolate H77)
|
3.1
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model.
Year : 2007
Volume : 51
Issue : 12
First Page : 4290
Last Page : 4296
Authors : Chen CM, He Y, Lu L, Lim HB, Tripathi RL, Middleton T, Hernandez LE, Beno DW, Long MA, Kati WM, Bosse TD, Larson DP, Wagner R, Lanford RE, Kohlbrenner WE, Kempf DJ, Pilot-Matias TJ, Molla A.
Abstract : A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.
|
Antiviral activity against HCV 1a H77 with NS5B polymerase G554D mutation infected in chimpanzee measured on day 16
|
Hepatitis C virus (isolate H77)
|
2.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model.
Year : 2007
Volume : 51
Issue : 12
First Page : 4290
Last Page : 4296
Authors : Chen CM, He Y, Lu L, Lim HB, Tripathi RL, Middleton T, Hernandez LE, Beno DW, Long MA, Kati WM, Bosse TD, Larson DP, Wagner R, Lanford RE, Kohlbrenner WE, Kempf DJ, Pilot-Matias TJ, Molla A.
Abstract : A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.
|
Antiviral activity against HCV 1a H77 with NS5B polymerase Y448C mutation infected in chimpanzee measured on day 28
|
Hepatitis C virus (isolate H77)
|
3.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model.
Year : 2007
Volume : 51
Issue : 12
First Page : 4290
Last Page : 4296
Authors : Chen CM, He Y, Lu L, Lim HB, Tripathi RL, Middleton T, Hernandez LE, Beno DW, Long MA, Kati WM, Bosse TD, Larson DP, Wagner R, Lanford RE, Kohlbrenner WE, Kempf DJ, Pilot-Matias TJ, Molla A.
Abstract : A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.
|
Antiviral activity against HCV2a J6/JFH1 infected in Huh7-5 cells at early T1 stage assessed as inhibition of core protein dimerization by RT PCR
|
Hepatitis C virus subtype 2a
|
72.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New small molecule inhibitors of hepatitis C virus.
Year : 2009
Volume : 19
Issue : 24
First Page : 6926
Last Page : 6930
Authors : Wei W, Cai C, Kota S, Takahashi V, Ni F, Strosberg AD, Snyder JK.
Abstract : New small molecule inhibitors of HCV were discovered by screening a small library of indoline alkaloid-type compounds. An automated assay format was employed which allowed identification of dimerization inhibitors of core, the capsid protein of the virus. These compounds were subsequently shown to block production of infectious virus in hepatoma cells.
|
Antiviral activity against HCV2a J6/JFH1 infected in Huh7-5 cells at late T2 stage assessed as inhibition of core protein dimerization by RT PCR
|
Hepatitis C virus subtype 2a
|
71.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New small molecule inhibitors of hepatitis C virus.
Year : 2009
Volume : 19
Issue : 24
First Page : 6926
Last Page : 6930
Authors : Wei W, Cai C, Kota S, Takahashi V, Ni F, Strosberg AD, Snyder JK.
Abstract : New small molecule inhibitors of HCV were discovered by screening a small library of indoline alkaloid-type compounds. An automated assay format was employed which allowed identification of dimerization inhibitors of core, the capsid protein of the virus. These compounds were subsequently shown to block production of infectious virus in hepatoma cells.
|
Inhibition of HCV NS3 protease by FRET assay
|
Hepatitis C virus
|
0.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents.
Year : 2010
Volume : 18
Issue : 14
First Page : 5413
Last Page : 5424
Authors : Lampa A, Ehrenberg AE, Gustafsson SS, Vema A, Kerblom E, Lindeberg G, Karlén A, Danielson UH, Sandström A.
Abstract : Phenylglycine has proved to be a useful P2 residue in HCV NS3 protease inhibitors. A novel pi-pi-interaction between the phenylglycine and the catalytic H57 residue of the protease is postulated. We hypothesized that the introduction of a vinyl on the phenylglycine might strengthen this pi-pi-interaction. Thus, herein is presented the synthesis and inhibitory potency of a series of acyclic vinylated phenylglycine-based HCV NS3 protease inhibitors. Surprisingly, inhibitors based on both D- and L-phenylglycine were found to be effective inhibitors, with a slight preference for the d-epimers. Furthermore, prime-side alkenylic extension of the C-terminal acylsulfonamide group gave significantly improved inhibitors with potencies in the nanomolar range (approximately 35 nM), potencies which were retained on mutant variants of the protease.
|
Antiviral activity against HCV 1B infected in human Huh7 cells by firefly luciferase reporter gene assay
|
Hepatitis C virus subtype 1b
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents.
Year : 2010
Volume : 18
Issue : 14
First Page : 5413
Last Page : 5424
Authors : Lampa A, Ehrenberg AE, Gustafsson SS, Vema A, Kerblom E, Lindeberg G, Karlén A, Danielson UH, Sandström A.
Abstract : Phenylglycine has proved to be a useful P2 residue in HCV NS3 protease inhibitors. A novel pi-pi-interaction between the phenylglycine and the catalytic H57 residue of the protease is postulated. We hypothesized that the introduction of a vinyl on the phenylglycine might strengthen this pi-pi-interaction. Thus, herein is presented the synthesis and inhibitory potency of a series of acyclic vinylated phenylglycine-based HCV NS3 protease inhibitors. Surprisingly, inhibitors based on both D- and L-phenylglycine were found to be effective inhibitors, with a slight preference for the d-epimers. Furthermore, prime-side alkenylic extension of the C-terminal acylsulfonamide group gave significantly improved inhibitors with potencies in the nanomolar range (approximately 35 nM), potencies which were retained on mutant variants of the protease.
|
Antiviral activity against Hepatitis C virus genotype 2a infected in mouse HB1 cell by cell-based HCV replicon assay in presence of 10% fetal bovine serum
|
Hepatitis C virus subtype 2a
|
27.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus genotype 1b infected in mouse HB1 cell by cell-based HCV replicon assay in presence of 50% normal human serum
|
Hepatitis C virus subtype 1b
|
17.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Antiviral activity against Hepatitis C virus genotype 1b infected in mouse HB1 cell by cell-based HCV replicon assay in presence of 10% fetal bovine serum
|
Hepatitis C virus subtype 1b
|
3.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Inhibition of Hepatitis C virus genotype 2b NS3/4A protease activity
|
Hepatitis C virus subtype 2b
|
61.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Inhibition of Hepatitis C virus genotype 2a NS3/4A protease activity
|
Hepatitis C virus subtype 2a
|
7.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease activity
|
Hepatitis C virus subtype 1b
|
0.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Inhibition of Hepatitis C virus genotype 1a NS3/4A protease activity
|
Hepatitis C virus subtype 1a
|
0.81
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
Year : 2010
Volume : 54
Issue : 1
First Page : 305
Last Page : 311
Authors : Liverton NJ, Carroll SS, Dimuzio J, Fandozzi C, Graham DJ, Hazuda D, Holloway MK, Ludmerer SW, McCauley JA, McIntyre CJ, Olsen DB, Rudd MT, Stahlhut M, Vacca JP.
Abstract : The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
|
Inhibition of HCV NS3 protease
|
Hepatitis C virus
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335).
Year : 2010
Volume : 53
Issue : 17
First Page : 6466
Last Page : 6476
Authors : Llinàs-Brunet M, Bailey MD, Goudreau N, Bhardwaj PK, Bordeleau J, Bös M, Bousquet Y, Cordingley MG, Duan J, Forgione P, Garneau M, Ghiro E, Gorys V, Goulet S, Halmos T, Kawai SH, Naud J, Poupart MA, White PW.
Abstract : C-Terminal carboxylic acid containing inhibitors of the NS3 protease are reported. A novel series of linear tripeptide inhibitors that are very potent and selective against the NS3 protease are described. A substantial contribution to the potency of these linear inhibitors arises from the introduction of a C8 substituent on the B-ring of the quinoline moiety found on the P2 of these inhibitors. The introduction of a C8 methyl group results not only in a modest increase in the cell-based potency of these inhibitors but more importantly in a much better pharmacokinetic profile in rats as well. Exploration of C8-substitutions led to the identification of the bromo derivative as the best group at this position, resulting in a significant increase in the cell-based potency of this class of inhibitors. Structure-activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotype1 NS3 protease with a promising PK profile in rats.
|
Antiviral activity against HCV Con1 by cell based-luciferase reporter gene assay
|
Hepatitis C virus
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335).
Year : 2010
Volume : 53
Issue : 17
First Page : 6466
Last Page : 6476
Authors : Llinàs-Brunet M, Bailey MD, Goudreau N, Bhardwaj PK, Bordeleau J, Bös M, Bousquet Y, Cordingley MG, Duan J, Forgione P, Garneau M, Ghiro E, Gorys V, Goulet S, Halmos T, Kawai SH, Naud J, Poupart MA, White PW.
Abstract : C-Terminal carboxylic acid containing inhibitors of the NS3 protease are reported. A novel series of linear tripeptide inhibitors that are very potent and selective against the NS3 protease are described. A substantial contribution to the potency of these linear inhibitors arises from the introduction of a C8 substituent on the B-ring of the quinoline moiety found on the P2 of these inhibitors. The introduction of a C8 methyl group results not only in a modest increase in the cell-based potency of these inhibitors but more importantly in a much better pharmacokinetic profile in rats as well. Exploration of C8-substitutions led to the identification of the bromo derivative as the best group at this position, resulting in a significant increase in the cell-based potency of this class of inhibitors. Structure-activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotype1 NS3 protease with a promising PK profile in rats.
|
Antiviral activity against wild-type Hepatitis C virus genotype 1b N infected in human Huh7 cells
|
Hepatitis C virus subtype 1b
|
1.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Relative replication capacity and selective advantage profiles of protease inhibitor-resistant hepatitis C virus (HCV) NS3 protease mutants in the HCV genotype 1b replicon system.
Year : 2008
Volume : 52
Issue : 3
First Page : 1101
Last Page : 1110
Authors : He Y, King MS, Kempf DJ, Lu L, Lim HB, Krishnan P, Kati W, Middleton T, Molla A.
Abstract : We characterized the selective advantage profiles of a panel of hepatitis C virus (HCV) NS3 protease mutants with three HCV protease inhibitors (PIs), BILN-2061, ITMN-191, and VX-950, using a genotype 1b HCV replicon system. Selective advantage curves were generated by a novel mathematical method that factors in the degree of drug susceptibility provided by the mutation, the base-level replication capacity of the mutant in the absence of drugs, and the overall viral replication levels as a function of drug concentration. Most of the mutants showed significantly increased selective advantages over the wild-type species upon drug treatment. Each drug is associated with unique selective advantage profiles that reflect its antiviral activity and mutant susceptibility. Five mutants (R155K/Q, A156T, and D168A/V) showed significant levels of selective advantage after treatment with >10 nM ( approximately 7 times the wild-type 50% effective concentration [EC50]) of BILN-2061. R155K displayed dominant levels of selective advantage over the other mutants upon treatment with ITMN-191 over a broad range of concentrations. Upon VX-950 treatment, various mutants (A156T, A156S, R155K, T54A, V170A, V36M/R155K, and R155Q) exhibited high levels of selective advantage in different drug concentration ranges, with A156T and A156S being the dominant mutants at >3 microM ( approximately 10 times the wild-type EC50) of VX-950. This method provides more accurate estimates of the behavior of various mutants under drug pressure than replication capacity analysis. We noted that the R155K mutant shows reduced susceptibility to all three PIs and significant selective advantage, raising concern over the potential emergence of R155K as a multidrug-resistant, highly fit mutant in HCV patients treated with PIs.
|
Antiviral activity against cyclosporine A/NIM811-resistant HCV subtype 1b Con1 infected in human HuH7 cells assessed as reduction in viral RNA level after 48 hrs by qRT-PCR analysis
|
Hepatitis C virus
|
1.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mechanism of resistance of hepatitis C virus replicons to structurally distinct cyclophilin inhibitors.
Year : 2010
Volume : 54
Issue : 5
First Page : 1981
Last Page : 1987
Authors : Puyang X, Poulin DL, Mathy JE, Anderson LJ, Ma S, Fang Z, Zhu S, Lin K, Fujimoto R, Compton T, Wiedmann B.
Abstract : The current standard of care for hepatitis C virus (HCV) infection, pegylated alpha interferon in combination with ribavirin, has a limited response rate and adverse side effects. Drugs targeting viral proteins are in clinical development, but they suffer from the development of high viral resistance. The inhibition of cellular proteins that are essential for viral amplification is thought to have a higher barrier to the emergence of resistance. Three cyclophilin inhibitors, the cyclosporine analogs DEBIO-025, SCY635, and NIM811, have shown promising results for the treatment of HCV infection in early clinical trials. In this study, we investigated the frequency and mechanism of resistance to cyclosporine (CsA), NIM811, and a structurally unrelated cyclophilin inhibitor, SFA-1, in replicon-containing Huh7 cells. Cross-resistance between all clones was observed. NIM811-resistant clones were selected only after obtaining initial resistance to either CsA or SFA-1. The time required to select resistance against cyclophilin inhibitors was significantly longer than that required for resistance selection against viral protein inhibitors, and the achievable resistance level was substantially lower. Resistance to cyclophilin inhibitors was mediated by amino acid substitutions in NS3, NS5A, and NS5B, with NS5A mutations conferring the majority of resistance. Mutation D320E in NS5A mediated most of the resistance conferred by NS5A. Taken together, the results indicate that there is a very low frequency and level of resistance to cyclophilin-binding drugs mediated by amino acid substitutions in three viral proteins. The interaction of cyclophilin with NS5A seems to be the most critical, since the NS5A mutations have the largest impact on resistance.
|
Antiviral activity against HCV subtype 1b Con1 infected in human HuH7 cells assessed as reduction in viral RNA level after 48 hrs by qRT-PCR analysis
|
Hepatitis C virus
|
1.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mechanism of resistance of hepatitis C virus replicons to structurally distinct cyclophilin inhibitors.
Year : 2010
Volume : 54
Issue : 5
First Page : 1981
Last Page : 1987
Authors : Puyang X, Poulin DL, Mathy JE, Anderson LJ, Ma S, Fang Z, Zhu S, Lin K, Fujimoto R, Compton T, Wiedmann B.
Abstract : The current standard of care for hepatitis C virus (HCV) infection, pegylated alpha interferon in combination with ribavirin, has a limited response rate and adverse side effects. Drugs targeting viral proteins are in clinical development, but they suffer from the development of high viral resistance. The inhibition of cellular proteins that are essential for viral amplification is thought to have a higher barrier to the emergence of resistance. Three cyclophilin inhibitors, the cyclosporine analogs DEBIO-025, SCY635, and NIM811, have shown promising results for the treatment of HCV infection in early clinical trials. In this study, we investigated the frequency and mechanism of resistance to cyclosporine (CsA), NIM811, and a structurally unrelated cyclophilin inhibitor, SFA-1, in replicon-containing Huh7 cells. Cross-resistance between all clones was observed. NIM811-resistant clones were selected only after obtaining initial resistance to either CsA or SFA-1. The time required to select resistance against cyclophilin inhibitors was significantly longer than that required for resistance selection against viral protein inhibitors, and the achievable resistance level was substantially lower. Resistance to cyclophilin inhibitors was mediated by amino acid substitutions in NS3, NS5A, and NS5B, with NS5A mutations conferring the majority of resistance. Mutation D320E in NS5A mediated most of the resistance conferred by NS5A. Taken together, the results indicate that there is a very low frequency and level of resistance to cyclophilin-binding drugs mediated by amino acid substitutions in three viral proteins. The interaction of cyclophilin with NS5A seems to be the most critical, since the NS5A mutations have the largest impact on resistance.
|
Antiviral activity against Hepatitis C virus genotype 1b in luciferase encoding genotype 1b replicons after 3 days by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
3.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel hepatitis C virus reporter replicon cell lines enable efficient antiviral screening against genotype 1a.
Year : 2010
Volume : 54
Issue : 8
First Page : 3099
Last Page : 3106
Authors : Robinson M, Yang H, Sun SC, Peng B, Tian Y, Pagratis N, Greenstein AE, Delaney WE.
Abstract : The hepatitis C virus (HCV) subgenomic replicon is the primary tool for evaluating the activity of anti-HCV compounds in drug discovery research. Despite the prevalence of HCV genotype 1a (approximately 70% of U.S. HCV patients), few genotype 1a reporter replicon cell lines have been described; this is presumably due to the low replication capacity of such constructs in available Huh-7 cells. In this report, we describe the selection of highly permissive Huh-7 cell lines that support robust replication of genotype 1a subgenomic replicons harboring luciferase reporter genes. These novel cell lines support the replication of multiple genotype 1a replicons (including the H77 and SF9 strains), are significantly more permissive to genotype 1a HCV replication than parental Huh7-Lunet cells, and maintain stable genotype 1a replication levels suitable for antiviral screening. We found that the sensitivity of genotype 1a luciferase replicons to known antivirals was highly consistent between individual genotype 1a clonal cell lines but could vary significantly between genotypes 1a and 1b. Sequencing of the nonstructural region of 12 stable replicon cell clones suggested that the enhanced permissivity is likely due to cellular component(s) in these new cell lines rather than the evolution of novel adaptive mutations in the replicons. These new reagents will enhance drug discovery efforts targeting genotype 1a and facilitate the profiling of compound activity among different HCV genotypes and subtypes.
|
Antiviral activity against Hepatitis C virus genotype 1a in luciferase encoding genotype 1a replicons after 3 days by luciferase reporter assay
|
Hepatitis C virus subtype 1a
|
17.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel hepatitis C virus reporter replicon cell lines enable efficient antiviral screening against genotype 1a.
Year : 2010
Volume : 54
Issue : 8
First Page : 3099
Last Page : 3106
Authors : Robinson M, Yang H, Sun SC, Peng B, Tian Y, Pagratis N, Greenstein AE, Delaney WE.
Abstract : The hepatitis C virus (HCV) subgenomic replicon is the primary tool for evaluating the activity of anti-HCV compounds in drug discovery research. Despite the prevalence of HCV genotype 1a (approximately 70% of U.S. HCV patients), few genotype 1a reporter replicon cell lines have been described; this is presumably due to the low replication capacity of such constructs in available Huh-7 cells. In this report, we describe the selection of highly permissive Huh-7 cell lines that support robust replication of genotype 1a subgenomic replicons harboring luciferase reporter genes. These novel cell lines support the replication of multiple genotype 1a replicons (including the H77 and SF9 strains), are significantly more permissive to genotype 1a HCV replication than parental Huh7-Lunet cells, and maintain stable genotype 1a replication levels suitable for antiviral screening. We found that the sensitivity of genotype 1a luciferase replicons to known antivirals was highly consistent between individual genotype 1a clonal cell lines but could vary significantly between genotypes 1a and 1b. Sequencing of the nonstructural region of 12 stable replicon cell clones suggested that the enhanced permissivity is likely due to cellular component(s) in these new cell lines rather than the evolution of novel adaptive mutations in the replicons. These new reagents will enhance drug discovery efforts targeting genotype 1a and facilitate the profiling of compound activity among different HCV genotypes and subtypes.
|
Antiviral activity against compound-resistant HCV genotype 1b infected in human Huh-9-13 cells assessed as reduction in viral replication after 3 days by quantitative RT-PCR
|
Hepatitis C virus subtype 1b
|
100.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Debio 025, a cyclophilin binding molecule, is highly efficient in clearing hepatitis C virus (HCV) replicon-containing cells when used alone or in combination with specifically targeted antiviral therapy for HCV (STAT-C) inhibitors.
Year : 2009
Volume : 53
Issue : 3
First Page : 967
Last Page : 976
Authors : Coelmont L, Kaptein S, Paeshuyse J, Vliegen I, Dumont JM, Vuagniaux G, Neyts J.
Abstract : Debio 025 is a potent inhibitor of hepatitis C virus (HCV) replication (J. Paeshuyse et al., Hepatology 43:761-770, 2006). In phase I clinical studies, monotherapy (a Debio 025 dose of 1,200 mg twice a day) resulted in a mean maximal decrease in the viral load of 3.6 log(10) units (R. Flisiak et al., Hepatology 47:817-826, 2008), whereas a reduction of 4.6 log(10) units was obtained in phase II studies when Debio 025 was combined with interferon (R. Flisiak et al., J. Hepatol., 48:S62, 2008). We here report on the particular characteristics of the in vitro anti-HCV activities of Debio 025. The combination of Debio 025 with either ribavirin or specifically targeted antiviral therapy for HCV (STAT-C) inhibitors (NS3 protease or NS5B [nucleoside and nonnucleoside] polymerase inhibitors) resulted in additive antiviral activity in short-term antiviral assays. Debio 025 has the unique ability to clear hepatoma cells from their HCV replicon when it is used alone or in combination with interferon and STAT-C inhibitors. Debio 025, when it was used at concentrations that have been observed in human plasma (0.1 or 0.5 muM), was able to delay or prevent the development of resistance to HCV protease inhibitors as well as to nucleoside and nonnucleoside polymerase inhibitors. Debio 025 forms an attractive drug candidate for the treatment of HCV infections in combination with standard interferon-based treatment and treatments that directly target the HCV polymerase and/or protease.
|
Antiviral activity against cyclosporine-resistant HCV genotype 1b infected in human Huh-9-13 cells assessed as reduction in viral replication after 3 days by quantitative RT-PCR
|
Hepatitis C virus subtype 1b
|
170.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Debio 025, a cyclophilin binding molecule, is highly efficient in clearing hepatitis C virus (HCV) replicon-containing cells when used alone or in combination with specifically targeted antiviral therapy for HCV (STAT-C) inhibitors.
Year : 2009
Volume : 53
Issue : 3
First Page : 967
Last Page : 976
Authors : Coelmont L, Kaptein S, Paeshuyse J, Vliegen I, Dumont JM, Vuagniaux G, Neyts J.
Abstract : Debio 025 is a potent inhibitor of hepatitis C virus (HCV) replication (J. Paeshuyse et al., Hepatology 43:761-770, 2006). In phase I clinical studies, monotherapy (a Debio 025 dose of 1,200 mg twice a day) resulted in a mean maximal decrease in the viral load of 3.6 log(10) units (R. Flisiak et al., Hepatology 47:817-826, 2008), whereas a reduction of 4.6 log(10) units was obtained in phase II studies when Debio 025 was combined with interferon (R. Flisiak et al., J. Hepatol., 48:S62, 2008). We here report on the particular characteristics of the in vitro anti-HCV activities of Debio 025. The combination of Debio 025 with either ribavirin or specifically targeted antiviral therapy for HCV (STAT-C) inhibitors (NS3 protease or NS5B [nucleoside and nonnucleoside] polymerase inhibitors) resulted in additive antiviral activity in short-term antiviral assays. Debio 025 has the unique ability to clear hepatoma cells from their HCV replicon when it is used alone or in combination with interferon and STAT-C inhibitors. Debio 025, when it was used at concentrations that have been observed in human plasma (0.1 or 0.5 muM), was able to delay or prevent the development of resistance to HCV protease inhibitors as well as to nucleoside and nonnucleoside polymerase inhibitors. Debio 025 forms an attractive drug candidate for the treatment of HCV infections in combination with standard interferon-based treatment and treatments that directly target the HCV polymerase and/or protease.
|
Antiviral activity against 2'-C-methyl-2'-fluoro-cytidine-resistant HCV genotype 1b infected in human Huh-9-13 cells assessed as reduction in viral replication after 3 days by quantitative RT-PCR
|
Hepatitis C virus subtype 1b
|
290.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Debio 025, a cyclophilin binding molecule, is highly efficient in clearing hepatitis C virus (HCV) replicon-containing cells when used alone or in combination with specifically targeted antiviral therapy for HCV (STAT-C) inhibitors.
Year : 2009
Volume : 53
Issue : 3
First Page : 967
Last Page : 976
Authors : Coelmont L, Kaptein S, Paeshuyse J, Vliegen I, Dumont JM, Vuagniaux G, Neyts J.
Abstract : Debio 025 is a potent inhibitor of hepatitis C virus (HCV) replication (J. Paeshuyse et al., Hepatology 43:761-770, 2006). In phase I clinical studies, monotherapy (a Debio 025 dose of 1,200 mg twice a day) resulted in a mean maximal decrease in the viral load of 3.6 log(10) units (R. Flisiak et al., Hepatology 47:817-826, 2008), whereas a reduction of 4.6 log(10) units was obtained in phase II studies when Debio 025 was combined with interferon (R. Flisiak et al., J. Hepatol., 48:S62, 2008). We here report on the particular characteristics of the in vitro anti-HCV activities of Debio 025. The combination of Debio 025 with either ribavirin or specifically targeted antiviral therapy for HCV (STAT-C) inhibitors (NS3 protease or NS5B [nucleoside and nonnucleoside] polymerase inhibitors) resulted in additive antiviral activity in short-term antiviral assays. Debio 025 has the unique ability to clear hepatoma cells from their HCV replicon when it is used alone or in combination with interferon and STAT-C inhibitors. Debio 025, when it was used at concentrations that have been observed in human plasma (0.1 or 0.5 muM), was able to delay or prevent the development of resistance to HCV protease inhibitors as well as to nucleoside and nonnucleoside polymerase inhibitors. Debio 025 forms an attractive drug candidate for the treatment of HCV infections in combination with standard interferon-based treatment and treatments that directly target the HCV polymerase and/or protease.
|
Antiviral activity against VX 950-resistant HCV genotype 1b infected in human Huh-9-13 cells assessed as reduction in viral replication after 3 days by quantitative RT-PCR
|
Hepatitis C virus subtype 1b
|
310.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Debio 025, a cyclophilin binding molecule, is highly efficient in clearing hepatitis C virus (HCV) replicon-containing cells when used alone or in combination with specifically targeted antiviral therapy for HCV (STAT-C) inhibitors.
Year : 2009
Volume : 53
Issue : 3
First Page : 967
Last Page : 976
Authors : Coelmont L, Kaptein S, Paeshuyse J, Vliegen I, Dumont JM, Vuagniaux G, Neyts J.
Abstract : Debio 025 is a potent inhibitor of hepatitis C virus (HCV) replication (J. Paeshuyse et al., Hepatology 43:761-770, 2006). In phase I clinical studies, monotherapy (a Debio 025 dose of 1,200 mg twice a day) resulted in a mean maximal decrease in the viral load of 3.6 log(10) units (R. Flisiak et al., Hepatology 47:817-826, 2008), whereas a reduction of 4.6 log(10) units was obtained in phase II studies when Debio 025 was combined with interferon (R. Flisiak et al., J. Hepatol., 48:S62, 2008). We here report on the particular characteristics of the in vitro anti-HCV activities of Debio 025. The combination of Debio 025 with either ribavirin or specifically targeted antiviral therapy for HCV (STAT-C) inhibitors (NS3 protease or NS5B [nucleoside and nonnucleoside] polymerase inhibitors) resulted in additive antiviral activity in short-term antiviral assays. Debio 025 has the unique ability to clear hepatoma cells from their HCV replicon when it is used alone or in combination with interferon and STAT-C inhibitors. Debio 025, when it was used at concentrations that have been observed in human plasma (0.1 or 0.5 muM), was able to delay or prevent the development of resistance to HCV protease inhibitors as well as to nucleoside and nonnucleoside polymerase inhibitors. Debio 025 forms an attractive drug candidate for the treatment of HCV infections in combination with standard interferon-based treatment and treatments that directly target the HCV polymerase and/or protease.
|
Antiviral activity against Hepatitis C virus genotype 1b infected in human Huh5-2 cells assessed as reduction in replicon RNA after 4 days by luciferase assay
|
Hepatitis C virus subtype 1b
|
40.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Comparative in vitro anti-hepatitis C virus activities of a selected series of polymerase, protease, and helicase inhibitors.
Year : 2008
Volume : 52
Issue : 9
First Page : 3433
Last Page : 3437
Authors : Paeshuyse J, Vliegen I, Coelmont L, Leyssen P, Tabarrini O, Herdewijn P, Mittendorfer H, Easmon J, Cecchetti V, Bartenschlager R, Puerstinger G, Neyts J.
Abstract : We report here a comparative study of the anti-hepatitis C virus (HCV) activities of selected (i) nucleoside polymerase, (ii) nonnucleoside polymerase, (iii) alpha,gamma-diketo acid polymerase, (iv) NS3 protease, and (v) helicase inhibitors, as well as (vi) cyclophilin binding molecules and (vii) alpha 2b interferon in four different HCV genotype 1b replicon systems.
|
Antiviral activity against Hepatitis C virus genotype 1b infected in human Huh-9-13 cells assessed as reduction in replicon RNA after 4days by RT-qPCR analysis
|
Hepatitis C virus subtype 1b
|
15.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Comparative in vitro anti-hepatitis C virus activities of a selected series of polymerase, protease, and helicase inhibitors.
Year : 2008
Volume : 52
Issue : 9
First Page : 3433
Last Page : 3437
Authors : Paeshuyse J, Vliegen I, Coelmont L, Leyssen P, Tabarrini O, Herdewijn P, Mittendorfer H, Easmon J, Cecchetti V, Bartenschlager R, Puerstinger G, Neyts J.
Abstract : We report here a comparative study of the anti-hepatitis C virus (HCV) activities of selected (i) nucleoside polymerase, (ii) nonnucleoside polymerase, (iii) alpha,gamma-diketo acid polymerase, (iv) NS3 protease, and (v) helicase inhibitors, as well as (vi) cyclophilin binding molecules and (vii) alpha 2b interferon in four different HCV genotype 1b replicon systems.
|
Antiviral activity against Hepatitis C virus genotype 1b infected in human HuH6 cells assessed as reduction in replicon RNA after 4days by RT-qPCR analysis
|
Hepatitis C virus subtype 1b
|
4.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Comparative in vitro anti-hepatitis C virus activities of a selected series of polymerase, protease, and helicase inhibitors.
Year : 2008
Volume : 52
Issue : 9
First Page : 3433
Last Page : 3437
Authors : Paeshuyse J, Vliegen I, Coelmont L, Leyssen P, Tabarrini O, Herdewijn P, Mittendorfer H, Easmon J, Cecchetti V, Bartenschlager R, Puerstinger G, Neyts J.
Abstract : We report here a comparative study of the anti-hepatitis C virus (HCV) activities of selected (i) nucleoside polymerase, (ii) nonnucleoside polymerase, (iii) alpha,gamma-diketo acid polymerase, (iv) NS3 protease, and (v) helicase inhibitors, as well as (vi) cyclophilin binding molecules and (vii) alpha 2b interferon in four different HCV genotype 1b replicon systems.
|
Antiviral activity against Hepatitis C virus genotype 1b infected in human Huh-Mono cells assessed as reduction in replicon RNA after 4 days by RT-qPCR analysis
|
Hepatitis C virus subtype 1b
|
10.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Comparative in vitro anti-hepatitis C virus activities of a selected series of polymerase, protease, and helicase inhibitors.
Year : 2008
Volume : 52
Issue : 9
First Page : 3433
Last Page : 3437
Authors : Paeshuyse J, Vliegen I, Coelmont L, Leyssen P, Tabarrini O, Herdewijn P, Mittendorfer H, Easmon J, Cecchetti V, Bartenschlager R, Puerstinger G, Neyts J.
Abstract : We report here a comparative study of the anti-hepatitis C virus (HCV) activities of selected (i) nucleoside polymerase, (ii) nonnucleoside polymerase, (iii) alpha,gamma-diketo acid polymerase, (iv) NS3 protease, and (v) helicase inhibitors, as well as (vi) cyclophilin binding molecules and (vii) alpha 2b interferon in four different HCV genotype 1b replicon systems.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing WT NS3 infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
0.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 V36L mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
1.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 V36M mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
2.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 V36A mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
1.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q41R mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
2.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 F43S mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
1.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 F43I mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
0.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 F43V mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
0.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 T54A mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
0.7
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 T54S mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
0.9
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80R mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
1.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80H mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
1.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80K mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
1.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80G mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
3.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80L mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
0.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R109K mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
1.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 S138T mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
0.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R155M mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
84.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R155I mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
29.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R155Q mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
248.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R155T mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
685.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 R155K mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
489.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 A156S mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
1.7
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 A156G mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
22.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168G mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
35.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168N mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
18.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168E mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
40.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168T mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
520.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168H mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
215.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 D168A mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
304.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 V170T mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
4.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 V170A mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
0.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 F43S and Q80R mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
0.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 F43S and D168E mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
5.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80K and R155K mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
705.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80R and R155K mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
707.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80R and D168E mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
87.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus subtype 1b expressing NS3 Q80H and D168E mutant infected in HuH7 cells after 48 hrs by by luciferase reporter assay
|
Hepatitis C virus subtype 1b
|
52.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.
Year : 2010
Volume : 54
Issue : 5
First Page : 1878
Last Page : 1887
Authors : Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A, Vermeiren K, Ivens T, Raboisson P, Edlund M, Storm S, Vrang L, de Kock H, Fanning GC, Simmen KA.
Abstract : TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
|
Antiviral activity against Hepatitis C virus JFH-1 J6 infected in human HuH7.5 cells assessed as inhibition of virus propagation measured after 72 hrs
|
Hepatitis C virus JFH-1
|
72.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent inhibitors of hepatitis C core dimerization as new leads for anti-hepatitis C agents.
Year : 2011
Volume : 21
Issue : 8
First Page : 2198
Last Page : 2202
Authors : Ni F, Kota S, Takahashi V, Strosberg AD, Snyder JK.
Abstract : New indoline alkaloid-type compounds which inhibit HCV production by infected hepatoma cells have been identified. These compounds, dimeric-type compounds of previously known inhibitors, display double digit nanomolar IC(50) and EC(50) values, with cytotoxicity CC(50) indexes higher than 36 μM, thus providing ample therapeutic windows for further development of HCV drugs.
|
Antiviral activity against Hepatitis C virus JFH-1 J6 infected in human HuH7.5 cells assessed as inhibition of virus propagation measured after 72 hrs of transfer to fresh media
|
Hepatitis C virus JFH-1
|
71.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent inhibitors of hepatitis C core dimerization as new leads for anti-hepatitis C agents.
Year : 2011
Volume : 21
Issue : 8
First Page : 2198
Last Page : 2202
Authors : Ni F, Kota S, Takahashi V, Strosberg AD, Snyder JK.
Abstract : New indoline alkaloid-type compounds which inhibit HCV production by infected hepatoma cells have been identified. These compounds, dimeric-type compounds of previously known inhibitors, display double digit nanomolar IC(50) and EC(50) values, with cytotoxicity CC(50) indexes higher than 36 μM, thus providing ample therapeutic windows for further development of HCV drugs.
|
Antiviral activity against HCV genotype 1b infected in Huh7 cells assessed as inhibition of viral replication by cell-based replicon assay
|
Hepatitis C virus subtype 1b
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel, potent, and orally bioavailable phosphinic acid inhibitors of the hepatitis C virus NS3 protease.
Year : 2011
Volume : 21
Issue : 12
First Page : 3568
Last Page : 3572
Authors : Clarke MO, Chen X, Cho A, Delaney WE, Doerffler E, Fardis M, Ji M, Mertzman M, Pakdaman R, Pyun HJ, Rowe T, Yang CY, Sheng XC, Kim CU.
Abstract : A potent and novel class of product-like inhibitors of the HCV NS3 protease was discovered by employing a phosphinic acid as a carboxylate isostere. The replicon activity and pharmacokinetic profile of this series of compounds was optimized by exploring the substitution of the phosphinic acid, as well as conformationally constraining these compounds through macrocyclization. The syntheses and preliminary biological evaluation of these phosphinic acids is described.
|
Inhibition of HCV 1a NS3/4A protease
|
Hepatitis C virus subtype 1a
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel, potent, and orally bioavailable phosphinic acid inhibitors of the hepatitis C virus NS3 protease.
Year : 2011
Volume : 21
Issue : 12
First Page : 3568
Last Page : 3572
Authors : Clarke MO, Chen X, Cho A, Delaney WE, Doerffler E, Fardis M, Ji M, Mertzman M, Pakdaman R, Pyun HJ, Rowe T, Yang CY, Sheng XC, Kim CU.
Abstract : A potent and novel class of product-like inhibitors of the HCV NS3 protease was discovered by employing a phosphinic acid as a carboxylate isostere. The replicon activity and pharmacokinetic profile of this series of compounds was optimized by exploring the substitution of the phosphinic acid, as well as conformationally constraining these compounds through macrocyclization. The syntheses and preliminary biological evaluation of these phosphinic acids is described.
|
Antiviral activity against HCV
|
Hepatitis C virus
|
350.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : P2-P1' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis.
Year : 2011
Volume : 19
Issue : 16
First Page : 4917
Last Page : 4927
Authors : Lampa A, Ehrenberg AE, Vema A, Åkerblom E, Lindeberg G, Danielson UH, Karlén A, Sandström A.
Abstract : Macrocyclization is a commonly used strategy to preorganize HCV NS3 protease inhibitors in their bioactive conformation. Moreover, macrocyclization generally leads to greater stability and improved pharmacokinetic properties. In HCV NS3 protease inhibitors, it has been shown to be beneficial to include a vinylated phenylglycine in the P2 position in combination with alkenylic P1' substituents. A series of 14-, 15- and 16-membered macrocyclic HCV NS3 protease inhibitors with the linker connecting the P2 phenylglycine and the alkenylic P1' were synthesized by ring-closing metathesis, using both microwave and conventional heating. Besides formation of the expected macrocycles in cis and trans configuration as major products, both ring-contracted and double-bond migrated isomers were obtained, in particular during formation of the smaller rings (14- and 15-membered rings). All inhibitors had K(i)-values in the nanomolar range, but only one inhibitor type was improved by rigidification. The loss in inhibitory effect can be attributed to a disruption of the beneficial π-π interaction between the P2 fragment and H57, which proved to be especially deleterious for the d-phenylglycine epimers.
|
Inhibition of HCV NS3 protease
|
Hepatitis C virus
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : P2-P1' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis.
Year : 2011
Volume : 19
Issue : 16
First Page : 4917
Last Page : 4927
Authors : Lampa A, Ehrenberg AE, Vema A, Åkerblom E, Lindeberg G, Danielson UH, Karlén A, Sandström A.
Abstract : Macrocyclization is a commonly used strategy to preorganize HCV NS3 protease inhibitors in their bioactive conformation. Moreover, macrocyclization generally leads to greater stability and improved pharmacokinetic properties. In HCV NS3 protease inhibitors, it has been shown to be beneficial to include a vinylated phenylglycine in the P2 position in combination with alkenylic P1' substituents. A series of 14-, 15- and 16-membered macrocyclic HCV NS3 protease inhibitors with the linker connecting the P2 phenylglycine and the alkenylic P1' were synthesized by ring-closing metathesis, using both microwave and conventional heating. Besides formation of the expected macrocycles in cis and trans configuration as major products, both ring-contracted and double-bond migrated isomers were obtained, in particular during formation of the smaller rings (14- and 15-membered rings). All inhibitors had K(i)-values in the nanomolar range, but only one inhibitor type was improved by rigidification. The loss in inhibitory effect can be attributed to a disruption of the beneficial π-π interaction between the P2 fragment and H57, which proved to be especially deleterious for the d-phenylglycine epimers.
|
Inhibition of HCV1b NS3/4A protease
|
Hepatitis C virus subtype 1b
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of GS-9256: a novel phosphinic acid derived inhibitor of the hepatitis C virus NS3/4A protease with potent clinical activity.
Year : 2012
Volume : 22
Issue : 3
First Page : 1394
Last Page : 1396
Authors : Sheng XC, Casarez A, Cai R, Clarke MO, Chen X, Cho A, Delaney WE, Doerffler E, Ji M, Mertzman M, Pakdaman R, Pyun HJ, Rowe T, Wu Q, Xu J, Kim CU.
Abstract : A potent and novel class of phosphinic acid derived product-like inhibitors of the HCV NS3/4A protease was discovered previously. Modification of the phosphinic acid and quinoline heterocycle led to GS-9256 with potent cell-based activity and favorable pharmacokinetic parameters. Based on these attributes, GS-9256 was advanced to human clinical trial as a treatment for chronic infection with genotype 1 HCV.
|
Antiviral activity against HCV genotype 1b infected in human Huh cells expressing luc gene by replicon assay
|
Hepatitis C virus subtype 1b
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of GS-9256: a novel phosphinic acid derived inhibitor of the hepatitis C virus NS3/4A protease with potent clinical activity.
Year : 2012
Volume : 22
Issue : 3
First Page : 1394
Last Page : 1396
Authors : Sheng XC, Casarez A, Cai R, Clarke MO, Chen X, Cho A, Delaney WE, Doerffler E, Ji M, Mertzman M, Pakdaman R, Pyun HJ, Rowe T, Wu Q, Xu J, Kim CU.
Abstract : A potent and novel class of phosphinic acid derived product-like inhibitors of the HCV NS3/4A protease was discovered previously. Modification of the phosphinic acid and quinoline heterocycle led to GS-9256 with potent cell-based activity and favorable pharmacokinetic parameters. Based on these attributes, GS-9256 was advanced to human clinical trial as a treatment for chronic infection with genotype 1 HCV.
|
Inhibition of Hepatitis C virus genotype 1b NS3/4A protease
|
Hepatitis C virus subtype 1b
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of GS-9451: an acid inhibitor of the hepatitis C virus NS3/4A protease.
Year : 2012
Volume : 22
Issue : 7
First Page : 2629
Last Page : 2634
Authors : Sheng XC, Appleby T, Butler T, Cai R, Chen X, Cho A, Clarke MO, Cottell J, Delaney WE, Doerffler E, Link J, Ji M, Pakdaman R, Pyun HJ, Wu Q, Xu J, Kim CU.
Abstract : The discovery of GS-9451 is reported. Modification of the P3 cap and P2 quinoline with a series of solubilizing groups led to the identification of potent HCV NS3 protease inhibitors with greatly improved pharmacokinetic properties in rats, dogs and monkeys.
|
Antiviral activity against Hepatitis C virus genotype 1b infected in human Huh cells by luciferase reporter gene based replicon assay
|
Hepatitis C virus subtype 1b
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of GS-9451: an acid inhibitor of the hepatitis C virus NS3/4A protease.
Year : 2012
Volume : 22
Issue : 7
First Page : 2629
Last Page : 2634
Authors : Sheng XC, Appleby T, Butler T, Cai R, Chen X, Cho A, Clarke MO, Cottell J, Delaney WE, Doerffler E, Link J, Ji M, Pakdaman R, Pyun HJ, Wu Q, Xu J, Kim CU.
Abstract : The discovery of GS-9451 is reported. Modification of the P3 cap and P2 quinoline with a series of solubilizing groups led to the identification of potent HCV NS3 protease inhibitors with greatly improved pharmacokinetic properties in rats, dogs and monkeys.
|
Inhibition of HCV 1a protease 1a domain
|
Hepatitis C virus
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b by stable replicon assay
|
Hepatitis C virus subtype 1b
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1a by stable replicon assay
|
Hepatitis C virus subtype 1a
|
2.2
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b harboring protease D168V mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
438.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b harboring protease D168A mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
205.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b harboring protease A156V mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
627.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b harboring protease A156T mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
604.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b harboring protease A156S mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against wild type Hepatitis C virus subtype 1b by transient replicon assay
|
Hepatitis C virus subtype 1b
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against Hepatitis C virus subtype 1b harboring protease R155K mutant by transient replicon assay
|
Hepatitis C virus subtype 1b
|
241.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
Year : 2012
Volume : 55
Issue : 7
First Page : 3021
Last Page : 3026
Authors : Kazmierski WM, Hamatake R, Duan M, Wright LL, Smith GK, Jarvest RL, Ji JJ, Cooper JP, Tallant MD, Crosby RM, Creech K, Wang A, Li X, Zhang S, Zhang YK, Liu Y, Ding CZ, Zhou Y, Plattner JJ, Baker SJ, Bu W, Liu L.
Abstract : The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
|
Antiviral activity against HCV1b by cell based replicon assay
|
Hepatitis C virus subtype 1b
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.
Year : 2011
Volume : 54
Issue : 7
First Page : 1961
Last Page : 2004
Authors : Marsault E, Peterson ML.
|
Antiviral activity against HCV1a by cell based replicon assay
|
Hepatitis C virus subtype 1a
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.
Year : 2011
Volume : 54
Issue : 7
First Page : 1961
Last Page : 2004
Authors : Marsault E, Peterson ML.
|
Inhibition of HCV 1a NS3 protease
|
Hepatitis C virus subtype 1a
|
0.3
nM
|
|
Journal : J. Med. Chem.
Title : Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.
Year : 2011
Volume : 54
Issue : 7
First Page : 1961
Last Page : 2004
Authors : Marsault E, Peterson ML.
|
Inhibition of HCV 1b NS3 protease
|
Hepatitis C virus subtype 1b
|
0.66
nM
|
|
Journal : J. Med. Chem.
Title : Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery.
Year : 2011
Volume : 54
Issue : 7
First Page : 1961
Last Page : 2004
Authors : Marsault E, Peterson ML.
|
Inhibition of Hepatitis C virus genotype 3a full-length NS3 protease assessed as overall/observed affinity by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 3a
|
160.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1b NS3 protease domain assessed as overall/observed affinity by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1b
|
2.5
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1b full-length NS3/NS4A protease assessed as overall/observed affinity by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1b
|
71.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1b full-length NS3 protease assessed as overall/observed affinity by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1b
|
67.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1a full-length NS3/NS4A protease assessed as overall/observed affinity by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1a
|
2.1
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1a full-length NS3 protease assessed as overall/observed affinity by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1a
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1b NS3 protease domain assessed as equilibrium dissociation constant by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1b
|
7.3
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1b full-length NS3/NS4A protease assessed as equilibrium dissociation constant by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1b
|
71.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1b full-length NS3 protease assessed as equilibrium dissociation constant by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1b
|
220.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1a full-length NS3/NS4A protease assessed as equilibrium dissociation constant by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1a
|
2.1
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Inhibition of Hepatitis C virus genotype 1a full-length NS3 protease assessed as equilibrium dissociation constant by surface plasmon resonance biosensor-based interaction kinetic analysis
|
Hepatitis C virus subtype 1a
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of weak points of hepatitis C virus NS3 protease inhibitors using surface plasmon resonance biosensor-based interaction kinetic analysis and genetic variants.
Year : 2014
Volume : 57
Issue : 5
First Page : 1802
Last Page : 1811
Authors : Svahn Gustafsson S, Ehrenberg A, Schmuck B, Anwar MI, Danielson UH.
Abstract : To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K(D)* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K(D)* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K(D)* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.
|
Antiviral activity against Hepatitis C virus genotype 1b infected in human HuH7 cells by subgenomic replicon-based luciferase assay
|
Hepatitis C virus subtype 1b
|
4.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2-P1' Region.
Year : 2014
Volume : 5
Issue : 3
First Page : 249
Last Page : 254
Authors : Lampa AK, Bergman SM, Gustafsson SS, Alogheli H, Akerblom EB, Lindeberg GG, Svensson RM, Artursson P, Danielson UH, Karlén A, Sandström A.
Abstract : Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1' 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with K i-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2-P1'. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1' 4-(trifluoromethyl)phenyl side chain.
|
Inhibition of Hepatitis C virus genotype 1a full length NS3/2K-NS4A protease using Ac-DED(Edans)EEAbupsi[COO]ASK(Dabcyl)-NH2 as substrate incubated for 10 mins prior to substrate addition by FRET analysis
|
Hepatitis C virus subtype 1a
|
0.3
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2-P1' Region.
Year : 2014
Volume : 5
Issue : 3
First Page : 249
Last Page : 254
Authors : Lampa AK, Bergman SM, Gustafsson SS, Alogheli H, Akerblom EB, Lindeberg GG, Svensson RM, Artursson P, Danielson UH, Karlén A, Sandström A.
Abstract : Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1' 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with K i-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2-P1'. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1' 4-(trifluoromethyl)phenyl side chain.
|
Inhibition of full-length HCV NS3 protease R155K mutant
|
Hepatitis C virus
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Achiral pyrazinone-based inhibitors of the hepatitis C virus NS3 protease and drug-resistant variants with elongated substituents directed toward the S2 pocket.
Year : 2014
Volume : 57
Issue : 5
First Page : 1790
Last Page : 1801
Authors : Gising J, Belfrage AK, Alogheli H, Ehrenberg A, Åkerblom E, Svensson R, Artursson P, Karlén A, Danielson UH, Larhed M, Sandström A.
Abstract : Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1' position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R(6) substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R(6) substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.
|
Inhibition of full-length HCV NS3 protease D168V mutant
|
Hepatitis C virus
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Achiral pyrazinone-based inhibitors of the hepatitis C virus NS3 protease and drug-resistant variants with elongated substituents directed toward the S2 pocket.
Year : 2014
Volume : 57
Issue : 5
First Page : 1790
Last Page : 1801
Authors : Gising J, Belfrage AK, Alogheli H, Ehrenberg A, Åkerblom E, Svensson R, Artursson P, Karlén A, Danielson UH, Larhed M, Sandström A.
Abstract : Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1' position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R(6) substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R(6) substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.
|
Inhibition of full-length HCV NS3 protease A156T mutant
|
Hepatitis C virus
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : Achiral pyrazinone-based inhibitors of the hepatitis C virus NS3 protease and drug-resistant variants with elongated substituents directed toward the S2 pocket.
Year : 2014
Volume : 57
Issue : 5
First Page : 1790
Last Page : 1801
Authors : Gising J, Belfrage AK, Alogheli H, Ehrenberg A, Åkerblom E, Svensson R, Artursson P, Karlén A, Danielson UH, Larhed M, Sandström A.
Abstract : Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1' position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R(6) substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R(6) substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.
|
Inhibition of full-length wild-type HCV NS3 protease
|
Hepatitis C virus
|
0.089
nM
|
|
Journal : J. Med. Chem.
Title : Achiral pyrazinone-based inhibitors of the hepatitis C virus NS3 protease and drug-resistant variants with elongated substituents directed toward the S2 pocket.
Year : 2014
Volume : 57
Issue : 5
First Page : 1790
Last Page : 1801
Authors : Gising J, Belfrage AK, Alogheli H, Ehrenberg A, Åkerblom E, Svensson R, Artursson P, Karlén A, Danielson UH, Larhed M, Sandström A.
Abstract : Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1' position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R(6) substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R(6) substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.
|
Inhibition of HCV genotype 1a NS3/4A protease using Ac-DED(Edans)EEAbu-psi[COO]ASK(Dabcyl)-NH2 as substrate by FRET assay
|
Hepatitis C virus subtype 1a
|
0.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles.
Year : 2014
Volume : 22
Issue : 23
First Page : 6595
Last Page : 6615
Authors : Lampa A, Alogheli H, Ehrenberg AE, Åkerblom E, Svensson R, Artursson P, Danielson UH, Karlén A, Sandström A.
Abstract : With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties.
|
Antiviral activity against HCV genotype 1a
|
Hepatitis C virus subtype 1a
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles.
Year : 2014
Volume : 22
Issue : 23
First Page : 6595
Last Page : 6615
Authors : Lampa A, Alogheli H, Ehrenberg AE, Åkerblom E, Svensson R, Artursson P, Danielson UH, Karlén A, Sandström A.
Abstract : With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties.
|
Inhibition of full length Hepatitis C virus genotype 1b Con1 NS3/4A by FRET assay
|
Hepatitis C virus (isolate Con1)
|
0.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design of a novel series of azetidine inhibitors of the hepatitis C virus NS3/4A serine protease.
Year : 2014
Volume : 24
Issue : 18
First Page : 4444
Last Page : 4449
Authors : Parsy C, Alexandre FR, Brandt G, Caillet C, Cappelle S, Chaves D, Convard T, Derock M, Gloux D, Griffon Y, Lallos L, Leroy F, Liuzzi M, Loi AG, Moulat L, Musiu C, Rahali H, Roques V, Seifer M, Standring D, Surleraux D.
Abstract : Structural homology between thrombin inhibitors and the early tetrapeptide HCV protease inhibitor led to the bioisosteric replacement of the P2 proline by a 2,4-disubstituted azetidine within the macrocyclic β-strand mimic. Molecular modeling guided the design of the series. This approach was validated by the excellent activity and selectivity in biochemical and cell based assays of this novel series and confirmed by the co-crystal structure of the inhibitor with the NS3/4A protein (PDB code: 4TYD).
|
Antiviral activity against Hepatitis C virus genotype 1b Con1 infected in human Huh7 cells assessed as inhibition of NS4A expression by ELISA
|
Hepatitis C virus (isolate Con1)
|
2.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design of a novel series of azetidine inhibitors of the hepatitis C virus NS3/4A serine protease.
Year : 2014
Volume : 24
Issue : 18
First Page : 4444
Last Page : 4449
Authors : Parsy C, Alexandre FR, Brandt G, Caillet C, Cappelle S, Chaves D, Convard T, Derock M, Gloux D, Griffon Y, Lallos L, Leroy F, Liuzzi M, Loi AG, Moulat L, Musiu C, Rahali H, Roques V, Seifer M, Standring D, Surleraux D.
Abstract : Structural homology between thrombin inhibitors and the early tetrapeptide HCV protease inhibitor led to the bioisosteric replacement of the P2 proline by a 2,4-disubstituted azetidine within the macrocyclic β-strand mimic. Molecular modeling guided the design of the series. This approach was validated by the excellent activity and selectivity in biochemical and cell based assays of this novel series and confirmed by the co-crystal structure of the inhibitor with the NS3/4A protein (PDB code: 4TYD).
|
Inhibition of full length HCV 1b Con1 NS3/4A protease using HiLyte Fluor 610 peptide substrate by biochemical FRET assay
|
Hepatitis C virus (isolate Con1)
|
0.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral evaluation of a novel series of homoserine-based inhibitors of the hepatitis C virus NS3/4A serine protease.
Year : 2015
Volume : 25
Issue : 18
First Page : 3984
Last Page : 3991
Authors : Alexandre FR, Brandt G, Caillet C, Chaves D, Convard T, Derock M, Gloux D, Griffon Y, Lallos L, Leroy F, Liuzzi M, Loi AG, Moulat L, Musiu C, Parsy C, Rahali H, Roques V, Seifer M, Standring D, Surleraux D.
Abstract : We disclose here the synthesis of a series of macrocyclic HCV protease inhibitors, where the homoserine linked together the quinoline P2' motif and the macrocyclic moiety. These compounds exhibit potent inhibitory activity against HCV NS3/4A protease and replicon cell based assay. Their enzymatic and antiviral activities are modulated by substitutions on the quinoline P2' at position 8 by methyl and halogens and by small heterocycles at position 2. The in vitro structure activity relationship (SAR) studies and in vivo pharmacokinetic (PK) evaluations of selected compounds are described herein.
|
Antiviral activity against HCV Con1 infected in human GS4.1 cells containing HCV Con1 subgenomic replicon assessed as reduction in NS5A protein expression by ELISA method
|
Hepatitis C virus (isolate Con1)
|
2.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral evaluation of a novel series of homoserine-based inhibitors of the hepatitis C virus NS3/4A serine protease.
Year : 2015
Volume : 25
Issue : 18
First Page : 3984
Last Page : 3991
Authors : Alexandre FR, Brandt G, Caillet C, Chaves D, Convard T, Derock M, Gloux D, Griffon Y, Lallos L, Leroy F, Liuzzi M, Loi AG, Moulat L, Musiu C, Parsy C, Rahali H, Roques V, Seifer M, Standring D, Surleraux D.
Abstract : We disclose here the synthesis of a series of macrocyclic HCV protease inhibitors, where the homoserine linked together the quinoline P2' motif and the macrocyclic moiety. These compounds exhibit potent inhibitory activity against HCV NS3/4A protease and replicon cell based assay. Their enzymatic and antiviral activities are modulated by substitutions on the quinoline P2' at position 8 by methyl and halogens and by small heterocycles at position 2. The in vitro structure activity relationship (SAR) studies and in vivo pharmacokinetic (PK) evaluations of selected compounds are described herein.
|
Inhibition of HCV genotype-3a full length NS3 protease preincubated for 10 mins followed by Ac-DED(Edans)EEAbuj-[COO]ASK(Dabcyl)-NH2 addition in presence of co-factor 2K-NS4A by fluorescence assay
|
Hepatitis C virus subtype 3a
|
20.0
nM
|
|
Journal : Eur J Med Chem
Title : Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold.
Year : 2018
Volume : 148
First Page : 453
Last Page : 464
Authors : Belfrage AK, Abdurakhmanov E, Åkerblom E, Brandt P, Alogheli H, Neyts J, Danielson UH, Sandström A.
Abstract : Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on β-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the β-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype 1a, both wild-type (Ki = 30 nM) and R155K (Ki = 2 nM), and genotype 3a (Ki = 5 nM).
|
Inhibition of HCV genotype-1a NS3 protease
|
Hepatitis C virus subtype 1a
|
0.089
nM
|
|
Journal : Eur J Med Chem
Title : Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold.
Year : 2018
Volume : 148
First Page : 453
Last Page : 464
Authors : Belfrage AK, Abdurakhmanov E, Åkerblom E, Brandt P, Alogheli H, Neyts J, Danielson UH, Sandström A.
Abstract : Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on β-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the β-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype 1a, both wild-type (Ki = 30 nM) and R155K (Ki = 2 nM), and genotype 3a (Ki = 5 nM).
|
Antiviral activity against HCV genotype 1b infected in human HuH7 cells
|
Hepatitis C virus subtype 1b
|
2.0
nM
|
|
Journal : Eur J Med Chem
Title : Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold.
Year : 2018
Volume : 148
First Page : 453
Last Page : 464
Authors : Belfrage AK, Abdurakhmanov E, Åkerblom E, Brandt P, Alogheli H, Neyts J, Danielson UH, Sandström A.
Abstract : Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on β-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the β-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype 1a, both wild-type (Ki = 30 nM) and R155K (Ki = 2 nM), and genotype 3a (Ki = 5 nM).
|
Antiviral activity against HCV
|
Hepatitis C virus
|
9.5
nM
|
|
Journal : Eur J Med Chem
Title : A review on HCV inhibitors: Significance of non-structural polyproteins.
Year : 2019
Volume : 164
First Page : 576
Last Page : 601
Authors : Ganta NM, Gedda G, Rathnakar B, Satyanarayana M, Yamajala B, Ahsan MJ, Jadav SS, Balaraju T.
Abstract : Hepatitis C virus (HCV) mortality and morbidity is a world health misery with an approximate 130-150 million chronically HCV tainted and suffering individuals and it initiate critical liver malfunction like cirrhosis, hepatocellular carcinoma or liver HCV cancer. HCV NS5B protein one of the best studied therapeutic target for the identification of new drug candidates to be added to the combination or multiple combination medication recently approved. During the past few years, NS5B has thus been an important object of attractive medicinal chemistry endeavors, which induced to the surfacing of betrothal preclinical drug molecules. In this scenario, the current review set limit to discuss research published on NS5B and few other therapeutic functional inhibitors concentrating on hit investigation, hit to lead optimization, ADME parameters evaluation, and the SAR data which was out for each compound type and similarity taken into consideration. The discussion outlined in this specific review will surly helpful and vital tool for those medicinal chemists investigators working with HCV research programs mainly pointing on NS5B and set broad spectrum identification of creative anti HCV compounds. This mini review also tells each and every individual compound ability related how much they are active against NS5B and few other targets.
