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

Phosphoramidate ProTides of 2′-C-Me-6-MeOG are up to 500-fold more potent versus HCV than the 2′-C-MeG parent, being active at nanomolar levels. The lead has entered phase 1 clinical trials for HCV. We herein report a novel double pro-drug approach applied to the anti-HCV agent 2′-β- 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 10 nM 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.