HCV NS5B polymerase inhibitors

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... 

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

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. 

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). 

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 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. 

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. 

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>. 

Several examples of this widely practiced name reaction have been applied in drug discovery abound. For example in a study describing the design and synthesis of inhibitors of hepatitis C virus (HCV) NS5B polymerase, thiazole intermediate was constructed via the Gabriel reaction, ... 

Discovery of NM-107 (6), the first HCV NS5B nucleoside polymerase inhibitor from Idenix Pharmaceuticals (now Merck), in combination with the discovery of 2 -deoxy-2 -fluorocytidine (7) by the Pharmasset research team led to the discovery of PSI-6130 (8). The metabolism study of PSI-6130 showed that PSI-6130 was anabolized to the active triphosphate, PSI-6130-TP (9), and two other metabolites, PSI-6206 (10, R02433, GS-331007) and PSI-6206-TP (11, PSI-7409, GS-461203). 2 The biological evaluation revealed that the triphosphate of PSI-6206 (11, PSI-7409, GS-461203) was a potent and selective inhibitor of HCV NS5B polymerase (IC90 = 0.52 pM), while PSI-6206 was inactive in the HCV rephcon assay (EC90 > 100 Subsequent... 

Sofosbuvir is the fu-st specific inhibitor of the HCV NS5B polymerase to come to the market. On December 6, 2013, the FDA approved SOF as a component of an antiviral combination regimen for the treatment of HCV genotypes 1, 2, 3, and 4. This was followed by approvals in Canada and the European Union (EU). Treatment was also approved for HCV persons co-infected with HIV-1, using SOF and RBV. In the EU, SOF is also approved for use in genotypes 5 and 6 in a 12-week regimen of SOF with PegIFN and RBV. 

Ruebsam F, Webber SE, Tran MT, Tran CV, Murphy DE, Zhao J, Dragovich PS, Kim SH, Li LS, Zhou Y, Han Q, Kissinger CR, Showalter RE, Lardy M, Shah AM, Tsan M, Patel R, Lebrun LA, Kamran R, Sergeeva MV, Bartkowski DM, Nolan TG, Norris DA, Kirkovsky L (2008) Pyrrolo[l,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase. Biooig Med Chem Lett 18 3616-3621... 

HCV infection Is a major health Issue with over 170 million carriers worldwide. Recently, we demonstrated potent clinical antiviral activity with R-7128, a prodrug of PSI-6130 (Beta-D-2 -deoxy-2 -fluoro-2 -C-methylcytidine). Cell metabolism studies have shown that PSI-6130-monophosphate is partially converted to its uridine metabolite, PSI-6206-monophosphate via cytidylate deaminase. The nucleoside, PSI-6206, by itself is not an inhibitor of HCV, however, PSI-6206-triphosphate is a potent inhibitor of HCV NS5B polymerase. 

In the search for novel and effective therapeutics for the treatment of HCV, HCV protease inhibitors are not the only class of enzyme inhibitor to which macrocyclization strategy has been applied. Thus, macrocyclic inhibitors of the HCV NS5B polymerase have also been explored (Section 7.6.1). In addition, macrocyclic analogs of acyclic inhibitors of proteases including. Factor XIa, HIV protease, renin and beta-secretase have been investigated. Examples of each of these are briefly discussed in Section 7.6.2. 

---