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

  • Bioorg Med Chem Lett. 2010 Aug 15;20(16):4850-4. doi: 10.1016/j.bmcl.2010.06.094.
Christopher McGuigan  1 ,  Karolina Madela ,  Mohamed Aljarah ,  Arnaud Gilles ,  Andrea Brancale ,  Nicola Zonta ,  Stanley Chamberlain ,  John Vernachio ,  Jeff Hutchins ,  Andrea Hall ,  Brenda Ames ,  Elena Gorovits ,  Babita Ganguly ,  Alexander Kolykhalov ,  Jin Wang ,  Jerry Muhammad ,  Joseph M Patti ,  Geoffrey Henson
Affiliations
  • 1. Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK. [email protected]
PMID: 20637609 DOI: 10.1016/j.bmcl.2010.06.094
Abstract

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 the lead compound INX-08189 was shown to be consistent with intracellular 2'-C-methyl guanosine triphosphate levels in primary human hepatocytes. The separated diastereomers of INX-08189 were shown to have similar activity in the replicon assay and were also shown to be similar substrates for enzyme processing. INX-08189 has completed investigational new drug enabling studies and has been progressed into human clinical trials for the treatment of chronic HCV Infection.

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