title: 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.
abstract: 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 of HCV therapies. β-d-2'-Deoxy-2'-α-fluoro-2'-β-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5'-phosphate derivative of the β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleoside were prepared and showed significant potency in the HCV subgenomic replicon assay (<1 μM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, 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.
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540, USA. michael.sofia@pharmasset.com
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sofia
authors.forename: Donghui
authors.initials: D
authors.lastname: Bao
authors.forename: Wonsuk
authors.initials: W
authors.lastname: Chang
authors.forename: Jinfa
authors.initials: J
authors.lastname: Du
authors.forename: Dhanapalan
authors.initials: D
authors.lastname: Nagarathnam
authors.forename: Suguna
authors.initials: S
authors.lastname: Rachakonda
authors.forename: P Ganapati
authors.initials: PG
authors.lastname: Reddy
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Ross
authors.forename: Peiyuan
authors.initials: P
authors.lastname: Wang
authors.forename: Hai-Ren
authors.initials: HR
authors.lastname: Zhang
authors.forename: Shalini
authors.initials: S
authors.lastname: Bansal
authors.forename: Christine
authors.initials: C
authors.lastname: Espiritu
authors.forename: Meg
authors.initials: M
authors.lastname: Keilman
authors.forename: Angela M
authors.initials: AM
authors.lastname: Lam
authors.forename: Holly M Micolochick
authors.initials: HM
authors.lastname: Steuer
authors.forename: Congrong
authors.initials: C
authors.lastname: Niu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Otto
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Furman
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D024882:Drug Resistance, Viral; D004952:Esters; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D009154:Mutation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012093:Replicon; D000069474:Sofosbuvir; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004952:Esters; D011355:Prodrugs; D000069474:Sofosbuvir; D014542:Uridine Monophosphate; D017361:Viral Nonstructural Proteins; C553297:2'-deoxy-2'-fluoro-2'-C-methyluridine 5'-monophosphate; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase