Use of 2'-spirocyclic ethers in HCV nucleoside design.
Conformationally restricted 2'-spironucleosides and their prodrugs were synthesized as potential anti-HCV agents. Although the replicon activity of the new agents containing pyrimidine bases was modest, the triphosphate of a 2'-oxetane cytidine analogue demonstrated potent intrinsic biochemical activity against the NS5B polymerase, with IC50 = 8.48 μM. Activity against NS5B bearing the S282T mutation was reduced. Phosphoramidate prodrugs of a 2'-oxetane 2-amino-6-O-methyl-purine nucleoside demonstrated potent anti-HCV activity in vitro, and the corresponding triphosphate retained similar potent activity against both wild-type and S282T HCV NS5B polymerase.
Pharmasset, Inc. , 303A College Road East, Princeton, New Jersey 08540, United States.
Jinfa
J
Du
Byoung-Kwon
BK
Chun
Ralph T
RT
Mosley
Shalini
S
Bansal
Haiying
H
Bao
Christine
C
Espiritu
Angela M
AM
Lam
Eisuke
E
Murakami
Congrong
C
Niu
Holly M
HM
Micolochick Steuer
Phillip A
PA
Furman
Michael J
MJ
Sofia
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003562:Cytidine / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D015195:Drug Design; D004987:Ethers / Q000737:chemistry; D016174:Hepacivirus / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization
D000998:Antiviral Agents; D004987:Ethers; D003562:Cytidine