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

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.

• Authors: Christopher McGuigan, 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
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 20 Issue 16 Pg. 4850-4 (Aug 15 2010) ISSN: 1464-3405 [Electronic] England
• PMID: 20637609 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Amides
• Antiviral Agents
• Phosphoric Acids
• Prodrugs
• Guanosine
• BMS-986094
• Guanosine Monophosphate
• phosphoramidic acid

Topics

• Amides (chemistry)
• Antiviral Agents (chemical synthesis, chemistry, toxicity)
• Cells, Cultured
• Drug Design
• Guanosine (analogs & derivatives, chemical synthesis, toxicity)
• Guanosine Monophosphate (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Hepacivirus (drug effects)
• Humans
• Phosphoric Acids (chemistry)
• Prodrugs (chemical synthesis, chemistry, toxicity)