title: A 2'-deoxy-2'-fluoro-2'-C-methyl uridine cyclopentyl carbocyclic analog and its phosphoramidate prodrug as inhibitors of HCV NS5B polymerase.
abstract: The 2 '-deoxy-2 '-fluoro-2 '-C-methyluridine nucleotide prodrug, PSI-7851 and its single diastereomer PSI-7977 have displayed potent antiviral activity against hepatitis C virus in clinical trials, and PSI-7977 is currently in Phase III studies. As part of our SAR study of the 2 '-deoxy-2 '-fluoro-2 '- C-methyl class of nucleosides, we prepared the cyclopentyl carbocyclic uridine analog 11 and its phosphoramidate prodrug 15. Both 11 and 15 were shown not to inhibit HCV replication. This lack of activity might be attributed to the inability of the monophosphate to be converted to the corresponding diphosphate or triphosphate or the inactivity of triphosphate of 11 as an inhibitor of the polymerase.
authors.affiliation: Pharmasset, Inc., Princeton, New Jersey 08540, USA. jamesliuworld@yahoo.com
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Jinfa
authors.initials: J
authors.lastname: Du
authors.forename: Peiyuan
authors.initials: P
authors.lastname: Wang
authors.forename: Dhanapalan
authors.initials: D
authors.lastname: Nagarathnam
authors.forename: Christine L
authors.initials: CL
authors.lastname: Espiritu
authors.forename: Haiying
authors.initials: H
authors.lastname: Bao
authors.forename: Eisuke
authors.initials: E
authors.lastname: Murakami
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Furman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sofia
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D003517:Cyclopentanes; D003857:Deoxyuridine; D009943:Organophosphorus Compounds; D011355:Prodrugs; D017361:Viral Nonstructural Proteins; C573696:1-(2-fluoro-3-hydroxy-4-(hydroxymethyl)-2-methylcyclopentyl)pyrimidine-2,4(1H,3H)-dione; C573697:isopropyl 2-((((4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-fluoro-2-hydroxy-3-methylcyclopentyl)methoxy)(phenoxy)phosphoryl)amino)propanoate; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase