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

✍ Scribed by 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

• Publisher: Elsevier Science
• Year: 2010
• Tongue: English
• Weight: 728 KB
• Volume: 20
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.06.094

✦ Synopsis

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.