title: Dual pro-drugs of 2'-C-methyl guanosine monophosphate as potent and selective inhibitors of hepatitis C virus.
abstract: We have previously reported the power of combining a 5'-phosphoramidate ProTide, phosphate pro-drug, motif with a 6-methoxy purine pro-drug entity to generate highly potent anti-HCV agents, leading to agents in clinical trial. We herein extend this work with the disclosure that a variety of alternative 6-substituents are tolerated. Several compounds exceed the potency of the prior 6-methoxy leads, and in almost every case the ProTide is several orders of magnitude more potent than the parent nucleoside. We also demonstrate that these agents act as pro-drugs of 2'-C-methyl guanosine monophosphate. We have also reported the novel use of hepatocyte cell lysate as an ex vivo model for ProTide metabolism.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK. mcguigan@cf.ac.uk
authors.forename: Christopher
authors.initials: C
authors.lastname: McGuigan
authors.forename: Karolina
authors.initials: K
authors.lastname: Madela
authors.forename: Mohamed
authors.initials: M
authors.lastname: Aljarah
authors.forename: Arnaud
authors.initials: A
authors.lastname: Gilles
authors.forename: Srinivas K
authors.initials: SK
authors.lastname: Battina
authors.forename: Changalvala V S
authors.initials: CV
authors.lastname: Ramamurty
authors.forename: C
authors.initials: C
authors.lastname: Srinivas Rao
authors.forename: John
authors.initials: J
authors.lastname: Vernachio
authors.forename: Jeff
authors.initials: J
authors.lastname: Hutchins
authors.forename: Andrea
authors.initials: A
authors.lastname: Hall
authors.forename: Alexander
authors.initials: A
authors.lastname: Kolykhalov
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Henson
authors.forename: Stanley
authors.initials: S
authors.lastname: Chamberlain
mesh_terms: D000659:AMP Deaminase / Q000378:metabolism; D000577:Amides / Q000737:chemistry / Q000378:metabolism; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010756:Phosphoric Acids / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000577:Amides; D000998:Antiviral Agents; C557801:IDX184; D009705:Nucleosides; D010756:Phosphoric Acids; D011355:Prodrugs; D006157:Guanosine Monophosphate; C011067:phosphoramidic acid; D000659:AMP Deaminase