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Review

Non-Nucleoside Inhibitors of Hepatitis C Virus Polymerase: Current Progress and Future Challenges

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Pages 121-141 | Published online: 22 Dec 2009

Bibliography

  • Neumann AU , LamNP, DahariHet al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy. Science 282(5386), 103–107 (1998).
  • Lee JH , NamIY, MyungH. Nonstructural protein 5B of hepatitis C virus.Mol. Cells21(3), 330–336 (2006).
  • Lesburg CA , CableMB, FerrariE, HongZ, MannarinoAF, WeberPC. Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site.Nat. Struct. Biol.6(10), 937–943 (1999).
  • Bressanelli S , TomeiL, RousselAet al. Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Proc. Natl Acad. Sci. USA 96(23), 13034–13039 (1999).
  • Ago H , AdachiT, YoshidaAet al. Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Structure 7(11), 1417–1426 (1999).
  • Koch U , NarjesF. Recent progress in the development of inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.Curr. Top. Med. Chem.7(13), 1302–1329 (2007).
  • De Francesco R , CarfiA. Advances in the development of new therapeutic agents targeting the NS3-4A serine protease or the NS5B RNA-dependent RNA polymerase of the hepatitis C virus.Adv. Drug Deliv. Rev.59(12), 1242–1262 (2007).
  • Beaulieu PL , TsantrizosYS. Inhibitors of the HCV NS5B polymerase: new hope for the treatment of hepatitis C infections.Curr. Opin. Investig. Drugs5(8), 838–850 (2004).
  • Carroll SS , OlsenDB. Nucleoside analog inhibitors of hepatitis C virus replication.Infect. Disord. Drug Targets6(1), 17–29 (2006).
  • Beaulieu PL . Recent advances in the development of NS5B polymerase inhibitors for the treatment of hepatitis C virus infection.Expert Opin. Ther. Pat.19(2), 145–164 (2009).
  • McCown MF , RajyaguruS, Le Pogam S et al. The hepatitis C virus replicon presents a higher barrier to resistance to nucleoside analogs than to nonnucleoside polymerase or protease inhibitors. Antimicrob. Agents Chemother.52(5), 1604–1612 (2008).
  • Toniutto P , FabrisC, BitettoD, FornasiereE, RapettiR, PirisiM. Valopicitabine dihydrochloride:a specific polymerase inhibitor of hepatitis C virus.Curr. Opin. Investig. Drugs.8(2), 150–158 (2007).
  • Carroll SS , DaviesME, HandtL. Robust suppression of viral replication by a nucleoside polymerase inhibitor in chimpanzees infected with hepatitis C virus.Hepatology44(Suppl. 1), 535A (2006).
  • Roberts SK , CooksleyG, DoreGJet al. Robust antiviral activity of R1626, a novel nucleoside analog: a randomized, placebo-controlled study in patients with chronic hepatitis C. Hepatology 48(2), 398–406 (2008).
  • Toniutto P , FabrisC, BitettoD, FumoloE, FornasiereE, PirisiM. R-1626, a specific oral NS5B polymerase inhibitor of hepatitis C virus.iDrugs11(10), 738–749 (2008).
  • Pockros PJ , NelsonD, GodofskyE. R1626 plus peginterferon α-2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin.Hepatology48(2), 385–397 (2008).
  • Hoffman La R oche. Roche Earnings Report (2008) [Press release].
  • Reddy R , Rodriguez-TorresM, GaneEet al. Antiviral activity, pharmacokinetics, safety and tolerability of R7128, a novel nucleoside HCV RNA polymerase inhibitor, following multiple, ascending oral doses in patients with HCV genotype 1 infection who have failed prior interferon therapy. Presented at: The 58th Annual Meeting of the American Association for the Study of Liver Diseases. MA, USA, 2–6 November 2007.
  • Lalezari J , GaneE, Rodriguez-TorresMet al. Potent antiviral activity of the HCV nucleoside polymerase inhibitor, R7128, in combination with PEG-IFN α-2a and ribavirin. Presented at: The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy23–27April2008.
  • Pharmasset (2008) [Press release].
  • Le Pogam S , SeshaadriA, KosakaAet al. No evidence of R7128 drug resistance after up to 4 weeks treatment of GT 1, 2 and 3 hepatitis C virus infected individuals. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, April22–262009.
  • Ali S , LevequeV, Le PogamSet al. Selected replicon variants with low-level in vitro resistance to the hepatitis C virus NS5B polymerase inhibitor PSI-6130 lack cross-resistance with R1479. Antimicrob. Agents Chemother.52(12), 4356–4369 (2008).
  • Pharmasset (2009) [Press release].
  • Zhou X-J , PietropaoloK, Sullivan-BolyaiJet al. IDX184, a liver-targeted nucleotide HCV polymerase inhibitor: results of a first-in-man safety and pharmacokinetic study. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver; Copenhagen, Denmark, 22–26April2009.
  • Standring DN , LanfordR, LiBet al. Antiviral activity of the liver-targeted nucleotide HCV polymerase inhibitor IDX184 correlates with trough serum levels of the nucleoside metabolite in HCV-infected chimpanzees. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Idenix (2009) [Press release].
  • Lin K , HazudaD, OttoMet al. Initial recommendations for HCV drug resistance analysis: a consensus statement from the HCV drug resistance advisory group. Presented at: HEPDART Frontiers in Drug Development for Viral Hepatitis. HI, USA, 9–13 December 2007.
  • Beaulieu PL . Finger loop inhibitors of the HCV NS5B polymerase: discovery and prospects for new HCV therapy.Curr. Opin. Drug Discov. Devel.9(5), 618–626 (2006).
  • Hirashima S , SuzukiT, IshidaTet al. Benzimidazole derivatives bearing substituted biphenyls as hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors: structure–activity relationship studies and identification of a potent and highly selective inhibitor JTK-109. J. Med. Chem. 49(15), 4721–4736 (2006).
  • Beaulieu PL , BösM, BousquetYet al. Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery of benzimidazole 5-carboxylic amide derivatives with low-nanomolar potency. Bioorg. Med. Chem. Lett. 14(4), 967–971 (2004).
  • Beaulieu PL , BousquetY, GauthierJet al. Non-nucleoside benzimidazole-based allosteric inhibitors of the hepatitis C virus NS5B polymerase: inhibition of subgenomic hepatitis C virus RNA replicons in Huh-7 cells. J. Med. Chem. 47(27), 6884–6892 (2004).
  • Beaulieu PL , GillardJ, BykowskiDet al. Improved replicon cellular activity of non-nucleoside allosteric inhibitors of HCV NS5B polymerase: from benzimidazole to indole scaffolds. Bioorg. Med. Chem. Lett. 16(19), 4987–4993 (2006).
  • Harper S , AvolioS, PaciniBet al. Potent inhibitors of subgenomic hepatitis C virus RNA replication through optimization of indole-N-acetamide allosteric inhibitors of the viral NS5B polymerase. J. Med. Chem. 48(14), 4547–4557 (2005).
  • Harper S , PaciniB, AvolioSet al. Development and preliminary optimization of indole-N-acetamide inhibitors of hepatitis C virus NS5B polymerase. J. Med. Chem. 48(5), 1314–1317 (2005).
  • Di Marco S , VolpariC, TomeiLet al. Interdomain communication in hepatitis C virus polymerase abolished by small molecule inhibitors bound to a novel allosteric site. J. Biol. Chem. 280(33), 29765–29770 (2005).
  • Giuliano C , FioreF, Di Marco A et al. Preclinical pharmacokinetics and metabolism of a potent non-nucleoside inhibitor of the hepatitis C virus NS5B polymerase. Xenobiotica35(10–11), 1035–1054 (2005).
  • Stansfield I , PompeiM, ConteIet al. Development of carboxylic acid replacements in indole-N-acetamide inhibitors of hepatitis C virus NS5B polymerase. Bioorg. Med. Chem. Lett. 17(18), 5143–5149 (2007).
  • Ikegashira K , OkaT, HirashimaSet al. Discovery of conformationally constrained tetracyclic compounds as potent hepatitis C virus NS5B RNA polymerase inhibitors. J. Med. Chem. 49(24), 6950–6953 (2006).
  • Stansfield I , ErcolaniC, MackayAet al. Tetracyclic indole inhibitors of hepatitis C virus NS5B-polymerase. Bioorg. Med. Chem. Lett. 19(3), 627–632 (2009).
  • Habermann J , CapitòE, Ferreira Mdel R, Koch U, Narjes F. Discovery of pentacyclic compounds as potent inhibitors of hepatitis C virus NS5B RNA polymerase. Bioorg. Med. Chem. Lett.19(3), 633–638 (2009).
  • Wedemeyer EH , BenhamouY, MollekenCet al. Safety, pharmacokinetics and antiviral effects of Boehringer Ingelheim BILB 1941, a novel HCV RNA polymerase, after 5 days oral treatment in patients with chronic hepatitis C. Presented at: The 42nd Annual Meeting of the European Association for the Study of Liver Diseases Barcelona, Spain, 11–15 April 2007.
  • De Francesco R , PaonessaG, OlsenDet al. Robust antiviral efficacy of a “finger-loop” allosteric inhibitor of the HCV polymerase in HCV infected chimpanzees. Presented at: HEPDART Frontiers in Drug Development for Viral Hepatitis. HI, USA, 9–13 December 2007.
  • Brainard D , WrightDH, SneddonKet al. Safety, tolerability and pharmacokinetics after single and multiple doses of MK-3281 in healthy subjects. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Love RA , PargeHE, YuXet al. Crystallographic identification of a noncompetitive inhibitor binding site on the hepatitis C virus NS5B RNA polymerase enzyme. J. Virol. 77(13), 7575–7581 (2003).
  • Love RA , MaegleyKA, YuXet al. The crystal structure of the RNA-dependent RNA polymerase from human rhinovirus: a dual function target for common cold antiviral therapy. Structure 12(8), 1533–1544 (2004).
  • Wang M , NgKK, CherneyMMet al. Non-nucleoside analogue inhibitors bind to an allosteric site on HCV NS5B polymerase. Crystal structures and mechanism of inhibition. J. Biol. Chem. 278(11), 9489–9495 (2003).
  • Li H , LintonA, TatlockJet al. Allosteric inhibitors of hepatitis C polymerase: discovery of potent and orally bioavailable carbon-linked dihydropyrones. J. Med. Chem. 50(17), 3969–3972 (2007).
  • Li H , TatlockJ, LintonAet al. Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors. Bioorg. Med. Chem. Lett. 16(18), 4834–4838 (2006).
  • Li H , TatlockJ, LintonAet al. Discovery of (R)-6-Cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor. J. Med. Chem. 52(5), 1255–1258 (2009).
  • Hammond JL , RosarioMC, WagnerFet al. Antiviral activity of the HCV polymerase inhibitor PF-00868554 administered as monotherapy in HCV genotype 1 infected subjects. Presented at: The 59th Annual Meeting of the American Association for the Study of Liver Diseases. CA, USA, 31 October–4 November 2008.
  • Shi ST , HerlihyKJ, GrahamJPet al. Preclinical characterization of PF-00868554, a potent nonnucleoside inhibitor of the hepatitis C virus RNA-dependent RNA polymerase. Antimicrob. Agents Chemother. 53(6), 2544–2552 (2009).
  • Troke P , LewisM, SimpsonPet al. Genotypic characterization of HCV NS5B following 8-day monotherapy with the polymerase inhibitor PF-00868554 in HCV-infected subjects. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Jacobson I , PockrosPJ, LalezariJet al. Antiviral activity of Filibuvir in combination with pegylated interferon alfa-2a and ribavirin for 28 days in treatment-naive patients chronically infected with HCV genotype 1. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Chan L , DasSK, ReddyTJet al. Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Part 1: sulfonamides. Bioorg. Med. Chem. Lett. 14(3), 793–796 (2004).
  • Chan L , PereiraO, ReddyTJet al. Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Part 2: tertiary amides. Bioorg. Med. Chem. Lett. 14(3), 797–800 (2004).
  • Cooper C , LawitzEJ, GhaliPet al. Evaluation of VCH-759 monotherapy in hepatitis C infection. J. Hepatol. 51(1), 39–46 (2009).
  • Lawitz E , CooperC, Rodriguez-TorresMet al. Safety, tolerability and antiviral activity of VCH-916, a novel non-nucleoside HCV polymerase inhibitor in patients with chronic HCV genotype-1 infection. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark 22–26 April 2009.
  • Nicolas O , BoivinI, Berneche-D‘AmoursAet al. Genotypic and phenotypic analysis of HCV NS5B variants selected from patients treated with VCH-916. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Bedard J , NicolasO, BilimoriaDet al. Identification and characterization of VCH-222, a novel potent and selective non-nucleoside HCV polymerase inhibitor. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Cooper C , LaroucheR, BourgaultB, ChauretN, ProulxL. Safety, tolerability and pharmacokinetics of the HCV polymerase inhibitor VCH-222 following single dose administration in healthy volunteers and antiviral activity in HCV-infected individuals. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Gopalsamy A , LimK, CiszewskiGet al. Discovery of pyrano[3,4-b]indoles as potent and selective HCV NS5B polymerase inhibitors. J. Med. Chem. 47(26), 6603–6608 (2004).
  • Gopalsamy A , ShiM, CiszewskiGet al. Design and synthesis of 2,3,4,9-tetrahydro-1H-carbazole and 1,2,3,4-tetrahydro-cyclopenta[b]indole derivatives as non-nucleoside inhibitors of hepatitis C virus NS5B RNA-dependent RNA polymerase. Bioorg. Med. Chem. Lett. 16(9), 2532–2534 (2006).
  • Gopalsamy A , AplascaA, CiszewskiGet al. Design and synthesis of 3,4-dihydro-1H-[1]-benzothieno[2,3-c]pyran and 3,4-dihydro-1H-pyrano[3,4-b]benzofuran derivatives as non-nucleoside inhibitors of HCV NS5B RNA dependent RNA polymerase. Bioorg. Med. Chem. Lett. 16(2), 457–460 (2006).
  • Howe AY , ChengH, ThompsonIet al. Molecular mechanism of a thumb domain hepatitis C virus nonnucleoside RNA-dependent RNA polymerase inhibitor. Antimicrob. Agents Chemother. 50(12), 4103–4113 (2006).
  • Pfefferkorn JA , GreeneML, NugentRAet al. Inhibitors of HCV NS5B polymerase. Part 1: evaluation of the southern region of (2Z)-2-(benzoylamino)-3-(5-phenyl-2-furyl)acrylic acid. Bioorg. Med. Chem. Lett. 15(10), 2481–2486 (2005).
  • Tedesco R . Discovery and optimization of 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase. Presented at: The 232nd American Chemistry Society National Meet. CA, USA, 10–14 September 2006.
  • Pratt JK , DonnerP, McDanielKFet al. Inhibitors of HCV NS5B polymerase: synthesis and structure-activity relationships of N-1-heteroalkyl-4-hydroxyquinolon-3-yl-benzothiadiazines. Bioorg. Med. Chem. Lett. 15(6), 1577–1582 (2005).
  • Rockway TW , ZhangR, LiuDet al. Inhibitors of HCV NS5B polymerase: synthesis and structure-activity relationships of N-1-benzyl and N-1-[3-methylbutyl]-4-hydroxy-1,8-naphthyridon-3-yl benzothiadiazine analogs containing substituents on the aromatic ring. Bioorg. Med. Chem. Lett. 16(14), 3833–3838 (2006).
  • Wagner R , LarsonDP, BenoDWet al. Inhibitors of hepatitis C virus polymerase: synthesis and biological characterization of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines. J. Med. Chem. 52(6), 1659–1669 (2009).
  • Randolph JT , FlentgeCA, HuangPPet al. Synthesis and biological characterization of B-ring amino analogues of potent benzothiadiazine hepatitis C virus polymerase inhibitors. J. Med. Chem. 52(10), 3174–3183 (2009).
  • Chen CM , HeY, LuLet al. Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model. Antimicrob. Agents Chemother. 51(12), 4290–4296 (2007).
  • Maring C , WagnerR, HutchinsonDet al. Preclinical potency, pharmacokinetic and ADME characterization of ABT-333, a novel non-nucleoside HCV polymerase inhibitor. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Wagner R , MaringC, DonnerPet al. Preclinical characterization of ABT-072: a novel non-nucleoside HCV polymerase inhibitor. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Koev G , MondalR, BeyerJet al. Characterization of resistance mutations selected in vitro by the non-nucleoside HCV polymerase inhibitors ABT-333 and ABT-072. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Menon R , CohenD, NadaAet al. Pharmacokinetics, safety and tolerability of the HCV polymerase inhibitor ABT-333 following multiple ascending doses and effect of co-administration of ketoconazole in healthy subjects. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Zhou Y , LiLS, DragovichPSet al. Novel HCV NS5B polymerase inhibitors derived from 4-(1´,1´-dioxo-1´,4´-dihydro-1´λ(6)-benzo[1´,2´,4´]thiadiazin-3´-yl)- 5-hydroxy-2H-pyridazin-3-ones. Part 2: variation of the 2- and 6-pyridazinone substituents. Bioorg. Med. Chem. Lett. 18(4), 1419–1424 (2008).
  • Zhou Y , WebberSE, MurphyDEet al. Novel HCV NS5B polymerase inhibitors derived from 4-(1´,1´-dioxo-1´,4´-dihydro-1´λ(6)-benzo[1´,2´,4´]thiadiazin-3´-yl)-5- hydroxy-2H-pyridazin-3-ones. Part 1: exploration of 7´-substitution of benzothiadiazine. Bioorg. Med. Chem. Lett. 18(4), 1413–1418 (2008).
  • Li LS , ZhouY, MurphyDEet al. Novel HCV NS5B polymerase inhibitors derived from 4-(1´,1´-dioxo-1´,4´-dihydro-1´λ(6)-benzo[1´,2´,4´]thiadiazin-3´-yl)- 5-hydroxy-2H-pyridazin-3-ones. Part 3: further optimization of the 2-, 6- and 7´-substituents and initial pharmacokinetic assessments. Bioorg. Med. Chem. Lett. 18(11), 3446–3455 (2008).
  • Ruebsam F , WebberSE, TranMTet al. Pyrrolo[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase. Bioorg. Med. Chem. Lett. 18(12), 3616–3621 (2008).
  • Ellis DA , BlazelJK, WebberSEet al. 4-(1,1-Dioxo-1,4-dihydro-1lambda6-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyr idazin-3-ones as potent inhibitors of HCV NS5B polymerase. Bioorg. Med. Chem. Lett. 18(16), 4628–4632 (2008).
  • Ruebsam F , SunZ, AyidaBKet al. Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase. Bioorg. Med. Chem. Lett. 18(18), 5002–5005 (2008).
  • Ruebsam F , TranCV, LiLSet al. 5,6-Dihydro-1H-pyridin-2-ones as potent inhibitors of HCV NS5B polymerase. Bioorg. Med. Chem. Lett. 19(2), 451–458 (2009).
  • Thompson PA , PatelRA, ShowalterRE, LiC, ApplemanJR, SteffyKR. In vitro studies demonstrate that combinations of antiviral agents that include HCV polymerase inhibitor ANA598 have the potential to overcome viral resistance. Presented at: The 59th Annual Meeting of the American Association for the Study of Liver Diseases. CA, USA, 31 October–4 November 2008.
  • Lawitz E , Rodriguez-TorresM, DeMiccoMet al. Antiviral activity of ANA598, a potent non-nucleoside polymerase inhibitor, in chronic hepatitis C patients. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26April2009.
  • Anadys (2009) [Press release].
  • Wang G , HeY, SunJet al. HCV NS5B polymerase inhibitors 1: synthesis and in vitro activity of 2-(1,1-dioxo-2H-[1,2,4]benzothiadiazin-3-yl)-1-hydroxynaphthalene derivatives. Bioorg. Med. Chem. Lett. 19(15), 4476–4479 (2009).
  • Wang G , LeiH, WangXet al. HCV NS5B polymerase inhibitors 2: synthesis and in vitro activity of (1,1-dioxo-2H-[1,2,4]benzothiadiazin-3-yl) azolo[1,5-a]pyridine and azolo[1,5-a]pyrimidine derivatives. Bioorg. Med. Chem. Lett. 19(15), 4480–4483 (2009).
  • Wang G , ZhangL, WuXet al. HCV NS5B polymerase inhibitors 3: synthesis and in vitro activity of 3-(1,1-dioxo-2H-[1,2,4]benzothiadiazin-3-yl)-4-hydroxy-2H-quinolizin-2-one derivatives. Bioorg. Med. Chem. Lett. 19(15), 4484–4487 (2009).
  • de Vicente J , HendricksRT, SmithDBet al. Non-nucleoside inhibitors of HCV polymerase NS5B. Part 4: structure-based design, synthesis and biological evaluation of benzo[d]isothiazole-1,1-dioxides. Bioorg. Med. Chem. Lett. 1(19), 5652–5656 (2009).
  • Hendricks RT , SpencerSR, BlakeJFet al. 3-hydroxyisoquinolines as inhibitors of HCV NS5b RNA-dependent RNA polymerase. Bioorg. Med. Chem. Lett. 19(2), 410–414 (2009).
  • Hendricks RT , FellJB, BlakeJFet al. Non-nucleoside inhibitors of HCV NS5B polymerase. Part 1: synthetic and computational exploration of the binding modes of benzothiadiazine and 1,4-benzothiazine HCV NS5b polymerase inhibitors. Bioorg. Med. Chem. Lett. 19(13), 3637–3641 (2009).
  • de Vicente J , HendricksRT, SmithDBet al. Non-nucleoside inhibitors of HCV polymerase NS5B. Part 2: synthesis and structure–activity relationships of benzothiazine-substituted quinolinediones. Bioorg. Med. Chem. Lett. 19(13), 3642–3646 (2009).
  • de Vicente J , HendricksRT, SmithDBet al. Non-nucleoside inhibitors of HCV polymerase NS5B. Part 3: synthesis and optimization studies of benzothiazine-substituted tetramic acids. Bioorg. Med. Chem. Lett. 1(19), 5648–5651 (2009).
  • Good SS , BuC, CamireMet al. Preclinical pharmacokinetic and safety profile of IDX375, a novel and potent non-nucleoside HCV polymerase inhibitor. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Bilello JP , StandringDN, DoussonCet al. In vitro activity and pharmacological properties of IDX375, a novel HCV non-nucleoside inhibitor. Presented at: The 59th Annual Meeting of the American Association for the Study of Liver Diseases. CA, USA, 31 October–4 November 2008.
  • Nittoli T , CurranK, InsafSet al. Identification of anthranilic acid derivatives as a novel class of allosteric inhibitors of hepatitis C NS5B polymerase. J. Med. Chem. 50(9), 2108–2116 (2007).
  • Gopalsamy A , ChopraR, LimKet al. Discovery of proline sulfonamides as potent and selective hepatitis C virus NS5b polymerase inhibitors. Evidence for a new NS5b polymerase binding site. J. Med. Chem. 49(11), 3052–3055 (2006).
  • Pfefferkorn JA , NugentR, GrossRJet al. Inhibitors of HCV NS5B polymerase. Part 2: evaluation of the northern region of (2Z)-2-benzoylamino-3-(4-phenoxy-phenyl)-acrylic acid. Bioorg. Med. Chem. Lett. 15(11), 2812–2818 (2005).
  • Slater MJ , AmphlettEM, AndrewsDMet al. Optimization of novel acyl pyrrolidine inhibitors of hepatitis C virus RNA-dependent RNA polymerase leading to a development candidate. J. Med. Chem. 50(5), 897–900 (2007).
  • McGowan D , NyanguileO, CummingsMDet al. 1,5-benzodiazepine inhibitors of HCV NS5B polymerase. Bioorg. Med. Chem. Lett. 19(9), 2492–2496 (2009).
  • Vandyck K , CummingsMD, NyanguileOet al. Structure-based design of a benzodiazepine scaffold yields a potent allosteric inhibitor of hepatitis C NS5B RNA polymerase. J. Med. Chem. 52(14), 4099–4102 (2009).
  • Gray F , AmphlettL, BrightHet al. GSK625433: a novel and highly potent inhibitor of the HCV NS5B polymerase. Presented at: The 42nd Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2007.
  • Hang JQ , YangY, HarrisSFet al. Slow binding inhibition and mechanism of resistance of non-nucleoside polymerase inhibitors of hepatitis C virus. J. Biol. Chem. 284(23), 15517–15529 (2009).
  • Villano S , HoweA, RaibleD, HarperD, SpethJ, BichierG. Analysis of HCV NS5B genetic variants following monotherapy with HCV-796, a non-nucleoside polymerase inhibitor, in treatment-naive HCV-infected patients.Hepatology44(4, Suppl. 1), A607–A608 (2006).
  • Pockros P , Rodriguez-TorresM, VillanoS, MallerE, ChojkierM. A Phase 2, randomized study of HCV-796 in combination with pegylated-interferon (PEG) plus ribavirin (RBV) versus PEG plus RBV in hepatitis C virus genotype-1 infection. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Vliegen I , PaeshuyseJ, De Burghgraeve T et al. Substituted imidazopyridines as potent inhibitors of HCV replication. J. Hepatol.50(5), 999–1009 (2009).
  • Shih I , VliegenI, PengBet al. Mechanistic characterization of GS-9190, a novel non-nucleoside inhibitor of HCV NS5B polymerase with potent antiviral activity and a unique mechanism of action. Presented at: The 58th Annual Meeting of the American Association for the Study of Liver Diseases. MA, USA, 2–6 November 2007.
  • Vliegen I , PaeshuyseJ, MarberyEet al. GS-9190, a novel substituted imidazopyridine analogue, is a potent inhibitor of hepatitis C virus replication in vitro and remains active against known drug resistant mutants. Presented at: The 58th Annual Meeting of the American Association for the Study of Liver Diseases. MA, USA, 2–6 November 2007.
  • Bavisotto L , WangCC, JacobsonIMet al. Antiviral, pharmacokinetic and safety data for GS-9190, a non-nucleoside HCV NS5b polymerase inhibitor, in a Phase-1 trial in HCV genotype 1 infected subjects. Presented at: The 58th Annual Meeting of the American Association for the Study of Liver Diseases. MA, USA, 2–6 November 2007.
  • Larrey D , BenhamouY, LohseAWet al. Safety, pharmacokinetics and antiviral effect of BI 207127, a novel HCV RNA polymerase inhibitor, after 5 days oral treatment in patients with chronic hepatitis C. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Seiwert SD , AndrewsSW, JiangYet al. Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227). Antimicrob. Agents Chemother. 52(12), 4432–4441 (2008).
  • Hutchinson DK , RosenbergT, KleinLLet al. Hepatitis C NS5B polymerase inhibitors: 4,4-Dialkyl-1-hydroxy-3-oxo-3,4-dihydronaphthalene-3-yl benzothiadiazine derivatives. Bioorg. Med. Chem. Lett. 18(14), 3887–3890 (2008).
  • Hagenbuch B , MeierJP. The superfamily of organic anion transporting polypeptides.Biochim. Biophys. Acta.1609(1), 1–18 (2003).
  • Feldstein A , KleinerD, KravetzD, BuckMet al. Severe hepatocellular injury with apoptosis induced by a hepatitis C polymerase inhibitor. J. Clin. Gastroenterol. 43(4), 374–381 (2009).
  • Rubino C , BradfordB, PorterS, ForrestA, BlattL, PatatA. Pharmacokinetic–pharmacodynamic (PK–PD) relationships for ITMN-191 in a Phase 1 multiple ascending dose (MAD) trial in patients with genotype 1 chronic hepatitis C infection. Presented at: The 59th Annual Meeting of the American Association for the Study of Liver Diseases. CA, USA, 31 October–1 November 2008.
  • McCown M , RajyaguruS, KularS, CammackN, NajeraI. Suppression of in vitro resistance development after treatment of the HCV replicon with NS3/4A inhibitor ITMN-191 (R7227) in combination with nucleoside inhibitor R7128 or R1626. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Gane EJ , RobertsSK, StedmanCet al. First-in-man demonstration of potent antiviral activity with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor combination in HCV: safety, pharmacokinetics and virologic results from INFORM-1. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Feldstein A , KleinerD, KravetzDet al. In vitro selected Con1 subgenomic replicons resistant to 2´-C-methyl-cytidine or to R1479 show lack of cross resistance. Virology351(2), 349–359 (2006).
  • Sofia M . Nucleoside approach to inhibitors for HCV polymerase. Presented at: The 2nd Annual Cambridge Healthtech Institute’s Drug Discovery Chemistry. CA, USA, 6–8 April 2009.
  • Marquis M , DeterdingK, ErhardtAet al. Genotypic and phenotypic analysis of hepatitis C virus NS5B polymerase variants to BILB1941 inhibition. Presented at: The 59th Annual Meeting of the American Association for the Study of Liver Diseases. CA, USA, 31 October–4 November 2008.
  • Thompson P , PatelR, SteffyK, ApplemanJ. Preclinical studies of ANA598 combined with other anti-HCV agents demonstrate potential of combination treatment. Presented at: The 44th Annual Meeting of the European Association for the Study of the Liver. Copenhagen, Denmark, 22–26 April 2009.
  • Le Pogam S , JiangWR, LevequeVet al. HCV796: a selective nonstructural protein 5B polymerase inhibitor with potent anti-hepatitis C virus activity in vitro, in mice with chimeric human livers and in humans infected with hepatitis C virus. Hepatology 49(3), 745–752 (2009).
  • Howe AY , ChengH, JohannSet al. Molecular mechanism of hepatitis C virus replicon variants with reduced susceptibility to a benzofuran inhibitor, HCV-796. Antimicrob. Agents Chemother. 52(9), 3327–3338 (2008).
  • Tedesco R , ShawAN, BambalRet al. 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase. J. Med. Chem. 49(3), 971–983 (2006).
  • Kati W , WagnerR, LuLet al. The antiviral efficacy of the nonnucleoside HCV polymerase inhibitor A-848837 in the HCV infected chimpanzee. Presented at: The 14th International Symposium on Hepatitis C Virus and Related Viruses. Glasgow, UK, 9–13 September 2007.
  • Kirkovsky L , ZhouY, NorrisDet al. ANA598, a novel non-nucleoside Inhibitor of HCV NS5B polymerase, exhibits favorable pharmacokinetic properties in multiple preclinical species. Presented at: The 58th Annual Meeting of the American Association for the Study of Liver Diseases. MA, USA, 2–6 November 2007.

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