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 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.
Sofia
Michael J
MJ
Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540, USA. michael.sofia@pharmasset.com
Bao
Donghui
D
Chang
Wonsuk
W
Du
Jinfa
J
Nagarathnam
Dhanapalan
D
Rachakonda
Suguna
S
Reddy
P Ganapati
PG
Ross
Bruce S
BS
Wang
Peiyuan
P
Zhang
Hai-Ren
HR
Bansal
Shalini
S
Espiritu
Christine
C
Keilman
Meg
M
Lam
Angela M
AM
Steuer
Holly M Micolochick
HM
Niu
Congrong
C
Otto
Michael J
MJ
Furman
Phillip A
PA
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
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