NS5B polymerase inhibitors

Currently, there is no approved antiviral therapy specifically targeting hepatitis C virus (HCV). The development of an HCV replicon system and our improved understanding of the structure and function of HCV proteins have led to the development of several classes of specific HCV inhibitors. NS3-4A protease inhibitors and NS5B polymerase inhibitors are furthest in development as discussed in Chaps. 2-4 (De and Migliaccio 2005 Manns et al. 2007 Pawlotsky et al. 2007). 

Table 2 Mutations associated with resistance to HCV NS5B polymerase inhibitors in vitro (Lin et al. 2007 Manns et al. 2007)...

HCV NS5B Polymerase Inhibitors in Combination with Interferons... 

HCV-796 is a non-nucleosidic NS5B polymerase inhibitor with potent antiviral activity in vitro. A phase lb study was performed to determine the antiviral activity, pharmacokinetics, and safety of HCV-796 in patients with chronic HCV infection. Maximum antiviral effects were achieved after 4 days of treatment with a mean reduction of HCV-RNA of 1.4 loglOIU/ml. Combination of HCV-796 with pegylated interferon-a led to a greater reduction of viral RNA load (3.3-3.5 loglO lU/ml) after a 14 days treatment interval. 

Structure-Based Library Design in Discovery of HCV NS5B Polymerase Inhibitors 3.4.1. Background... 

Isothiazoles have been incorporated into selective ChK2 (checkpoint kinase 2) inhibitor 212 <07BMCL172> and HCV (hepatitis C virus) NS5B polymerase inhibitor 213 <07BMCL28>, sultam into CDK (cyclin-dependent kinase) inhibitor 214 <07BMCL1284>, and trioxo-benzoisothiazole into the non-hepatotoxic acetaminophen analog 215 <07BMC2206>. 

N. Kaushik-Basu, A. Bopda-Waffo, T.T. Talele, A. Basu, P.R.R. Costa, A.J.M. da Silva, S.G. Sarafianos, F. Noel, Identification and characterization of coumestans as novel HCV NS5B polymerase inhibitors. Nucleic Acids Res. 36 (2008) 1482-1496. 

Kukolj G, McGibbon GA, McKercher G, Marquis M, Lefebvre S, Thauvette L, Gauthier J, Goulet S, Poupait MA, Beaulieu PL (2005) Binding site characterization and resistance to a class of non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase, J Biol Chem 280 39260-39267... 

TMN191 11. NS5B RNA-dependent RNA polymerase inhibitors InterMune/Roche Phase 1... 

Ikegashira et al. reported another recent example of the successful exploitation of conformational locks. They describe the discovery of a novel class of hepatitis C virus NS5B RNA polymerase inhibitors [42]. By designing and synthesizing conformationally constrained analogs of 40 (see Fig. 8.9), they obtained a series of novel compounds with significantly improved potency. Compound 41 was, for example, shown to be 7-fold more potent, see Fig. 8.9. 

Ishidaa, T., Suzuki, T., Hirashimaa, S., Mizutani, K., Yoshida, A., Ando, I., Ikeda, S., Adachi, T., Hashimoto, H. Benzimidazole inhibitors of hepatitis C virus NS5B polymerase identification of 2-[(4-diarylmethoxy)phenyl]-benzimidazole. Bioorg. Med. Chem. Lett. 2006, 36, 1859-1863. 

Structure-based design of a novel thiazolone scaffold as HCV NS5B polymerase allosteric inhibitors. Bioorg Med Chem Lett 16, 5888-5891. 15. 

Z., Hamatake, R. K., Hong, Z., Yao, N. (2007) Thiazolone-acylsulfonamides as novel HCV NS5B polymerase allosteric inhibitors 16. 

NS5B polymerase allosteric inhibitors Further designs, SAR, and X-ray complex structure. Bioorg Med Chem Lett 17, 63-67. 

Rong, F., Chow, S., Yan, S., Larson, G., Hong, Z., Wu, J. (2007) Structure-activity relationship (SAR) studies of quinoxalines as novel HCV NS5B RNA-dependent RNA polymerase inhibitors. Bioorg Med Chem Lett 17,1663-1666. 

N., Nguyen- , N., Alaoui-Ismaili, M. H., Bethell, R. C., James, M. N. (2003) Nonnucleoside analogue inhibitors bind to an allosteric site on HCV NS5B polymerase. Crystal structures and mechanism of inhibition. J Biol Chem 278, 9489-9495. 

Biswal, . K., Wang, M., Cherney, M. M., Chan, L., Yannopoulos, C. G., Bilimoria, D., Bedard, J., James, M. N. (2006) Nonnucleoside inhibitors binding to hepatitis C virus NS5B polymerase reveal a novel mechanism of inhibition. /Mol Biol 361, 33-45. 

Summa, V., Petrocchi, A., Matassa, V.G., Tabani, M., Laufer, R., Francessco, R.D., Altamura, S., and Pace, P. 2004. HCV NS5b RNA-dependent RNA polymerase inhibitors From a,y-diketoacids to 4,5-dihydroxypyrtmidine- or 3-methyl-5-hydroxypyrimidinonecar-boxylic acids. Design and synthesis. Journal of Medicinal Chemistry, 47 5336-39. 

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