Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus.

@article{McGuigan2010DesignSA,
  title={Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus.},
  author={Christopher McGuigan and Karolina Madela and Mohamed Aljarah and Arnaud Gilles and Andrea Brancale and Nicola Zonta and Stanley G. Chamberlain and John H. Vernachio and Jeff T. Hutchins and Andrea J. Atkinson Anne Fraser Benjamin D. Hall and Brenda R Ames and Elena Gorovits and Babita Ganguly and Alexander Kolykhalov and Jin Wang and Jerry L Muhammad and Joseph M. Patti and Geoffrey Henson},
  journal={Bioorganic & medicinal chemistry letters},
  year={2010},
  volume={20 16},
  pages={4850-4}
}
We herein report a novel double pro-drug approach applied to the anti-HCV agent 2'-beta-C-methyl guanosine. A phosphoramidate ProTide motif and a 6-O-methoxy base pro-drug moiety are combined to generate lipophilic prodrugs of the monophosphate of the guanine nucleoside. Modification of the ester and amino acid moieties lead to a compound INX-08189 that exhibits 10nM potency in the HCV genotype 1b subgenomic replicon, thus being 500 times more potent than the parent nucleoside. The potency of… CONTINUE READING

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