2'-deoxy-2'-α-fluoro-2'-β-C-methyl 3',5'-cyclic phosphate nucleotide prodrug analogs as inhibitors of HCV NS5B polymerase: discovery of PSI-352938.
A series of novel 2'-deoxy-2'-α-fluoro-2'-β-C-methyl 3',5'-cyclic phosphate nucleotide prodrug analogs were synthesized and evaluated for their in vitro anti-HCV activity and safety. These prodrugs demonstrated a 10-100-fold greater potency than the parent nucleoside in a cell-based replicon assay due to higher cellular triphosphate levels. Our structure-activity relationship (SAR) studies provided compounds that gave high levels of active triphosphate in rat liver when administered orally to rats. These studies ultimately led to the selection of the clinical development candidate 24a (PSI-352938).
Pharmasset, Inc., 303A College Road East, Princeton, NJ 08540, USA. pgreddy@pharmasset.com
P Ganapati
PG
Reddy
Donghui
D
Bao
Wonsuk
W
Chang
Byoung-Kwon
BK
Chun
Jinfa
J
Du
Dhanapalan
D
Nagarathnam
Suguna
S
Rachakonda
Bruce S
BS
Ross
Hai-Ren
HR
Zhang
Shalini
S
Bansal
Christine L
CL
Espiritu
Meg
M
Keilman
Angela M
AM
Lam
Congrong
C
Niu
Holly Micolochick
HM
Steuer
Phillip A
PA
Furman
Michael J
MJ
Otto
Michael J
MJ
Sofia
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003498:Cyclic P-Oxides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D008968:Molecular Conformation; D009705:Nucleosides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D009712:Nucleotides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D003498:Cyclic P-Oxides; D004791:Enzyme Inhibitors; D009705:Nucleosides; D009712:Nucleotides, Cyclic; D011355:Prodrugs; D017361:Viral Nonstructural Proteins; C556498:PSI 352938; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase