Discovery of a β-D-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus

Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment Of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development or HCV therapies. beta-D-2'-Deoxy-2'-alpha-fluoro-2 '-beta-C-methyl nucleosides arc selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5'-phosphate derivative of the beta-D-2'-deoxy-2'-alpha-fluoro-2'-beta-C-methyluridine nucleoside were prepared and showed significant potency in the HCV subgenomic replicon assay (<1 mu M) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers arms, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixture 14 was crystallized, and an X-ray structure was determined establishing the phosphoramidate stereochemistry as Sp, thus correlating for the first time the stereochemistry of a phosphoramidate prodrug with biological activity. 51 (PSI-7977) was selected as a clinical development candidate.