Pyrrolo[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase

https://doi.org/10.1016/j.bmcl.2008.04.066Get rights and content

Abstract

Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3k, which displayed potent inhibitory activities in biochemical and replicon assays (IC50 (1b) < 10 nM; EC50 (1b) = 12 nM) as well as good stability towards human liver microsomes (HLM t1/2 > 60 min).

Section snippets

Acknowledgments

The authors thank Drs. Devron Averett and Steve Worland for their support and helpful discussions during the course of this work.

References and notes (16)

  • M.J. Slater et al.

    J. Med. Chem.

    (2007)
    D. Dhanak et al.

    J. Biol. Chem.

    (2002)
    K.A. Evans et al.

    Bioorg. Med. Chem. Lett.

    (2006)
    (d)Blake, J. F.; Fell, J. B.; Fischer, J. P.; Hendricks, R. T.; Spencer, S. R.; Stengel, P. J. WO2006117306,...J.K. Pratt et al.

    Bioorg. Med. Chem. Lett.

    (2005)
    (f)Hutchinson, D. K. et al. U.S. Patent US2005107364,...
  • Ruebsam, F.; Tran, M. T.; Webber, S. E.; Dragovich, P. S.; Li, L.-S.; Murphy, D. E.; Kucera, D. J.; Sun, Z.; Tran, C....
  • W. Deng et al.

    Tetrahedron Lett.

    (2005)
  • W.R. Kim

    Hepatology

    (2002)
    M.J. Alter et al.

    N. Engl. J. Med.

    (1999)
    A. Alberti et al.

    J. Hepatol.

    (2003)
  • R.W. Sidwell et al.

    Science

    (1972)
    R.A. Smith et al.E. De Clercq

    Adv. Virus Res.

    (1993)
  • J.H. Hoofnagle et al.

    N. Eng. J. Med.

    (2007)
  • A.A. Kolykhalov et al.

    Science

    (1997)
There are more references available in the full text version of this article.

Cited by (38)

  • Design and development of HCV NS5B polymerase inhibitors

    2017, Viral Proteases and Their Inhibitors
  • Computational predictions suggest that structural similarity in viral polymerases may lead to comparable allosteric binding sites

    2016, Virus Research
    Citation Excerpt :

    Biochemical experiments combined with computational studies provide insight into how inhibitors bound to the HCV NNI-2 and NNI-3 pockets achieve allosteric inhibition. Both NNI-2 and NNI-3 inhibitors have been shown to disrupt an early stage of replication that precedes elongation (Ruebsam et al., 2008; Ontoria et al., 2009). Molecular simulations by our group suggest that inhibitors of the NNI-2 and NNI-3 pockets generally restrict protein fluctuations and disrupt motions observed in the free enzyme (Davis and Thorpe 2013; Brown and Thorpe, 2015; Davis et al., 2015).

  • The therapeutic journey of pyridazinone

    2016, European Journal of Medicinal Chemistry
    Citation Excerpt :

    Ellis et al. reported pyridazinone bearing compound, 68 as a potent inhibitor of HCV NS5B enzyme with IC50 value of less than 10 nM and CE50 of 1.1 nM [95]. Amongst the pyridazinone analogs prepared by Ruebsam et al., compound 69 displayed excellent potency against genotype 1 HCV NS5B polymerase [96]. Li et al. optimized, physical properties and pharmacokinetics parameters of pyridazinone moiety in a review article.

  • Allosteric inhibitors have distinct effects, but also common modes of action, in the HCV polymerase

    2015, Biophysical Journal
    Citation Excerpt :

    We confirmed that the ligands remained bound to the enzyme throughout the simulations via visual inspection of each trajectory. Fig. 1 shows the structures of each ligand and their corresponding IC50 values (19,21–24). Overall, ligand binding shifts the conformational sampling of the enzyme compared to the free structures, which is demonstrated by the distributions of interdomain angles (θ) and template channel widths shown in Fig. 2.

View all citing articles on Scopus
View full text