Discovery of a Series of 2′-α-Fluoro,2′-β-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus

Abstract

Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of β-D-2′-Br,2′-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pangenotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5′-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 μM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.

Repurposing Nucleoside Analogs for Human Coronaviruses

“…1 ). We selected several reported anti-HCV agents, such as 2′- C -methylcytidine (compound 2) ( 9 ), sofosbuvir (compound 4), a novel prodrug of sofosbuvir (compound 3) ( 10 ), and two 2′-dihalogeno nucleoside prodrugs (compounds 6 and 7) ( 11 , 12 ). We also selected ALS-8112 (compound 5) ( 13 ), the active form of lumicitabine, a drug developed until recently for the treatment of respiratory syncytial virus (RSV) ( 14 ).…”

Diastereoselective Synthesis of 2′-Dihalopyrimidine Ribonucleoside Inhibitors of Hepatitis C Virus Replication

“…We then turned our attention to the glycosylation step, which is one of the major limitations in the existing synthetic routes. Indeed, Vorbrüggen-type condensation (S N 1 mechanism) resulted in poor diastereoselectivities with β/α anomer ratios between 1/2 10 and 1/1. 11 We, therefore, sought to overcome this selectivity issue by introducing the nucleobase via an S N 2-type reaction.…”

Anno 2021: Which antivirals for the coming decade?

“…8 ). 203 This Sp phosphoramidate diastereomer of 2′-bromo,2′-fluoro-uridine exhibited potent inhibition of HCV in cell culture (EC 50 = 21–180 nM) combined with pan-genotypic anti-HCV replicon activity. Its corresponding 5′-triphosphate was selective for HCV NS5B polymerase of GT1-6 with no concomitant inhibition of human or cellular mitochondrial RNA polymerases, while exhibiting favorable liver accumulation according to a preliminary liver pharmacokinetic study in beagle dogs.…”