title: Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus.
abstract: We herein report a novel double pro-drug approach applied to the anti-HCV agent 2'-beta-C-methyl guanosine. A phosphoramidate ProTide motif and a 6-O-methoxy base pro-drug moiety are combined to generate lipophilic prodrugs of the monophosphate of the guanine nucleoside. Modification of the ester and amino acid moieties lead to a compound INX-08189 that exhibits 10nM potency in the HCV genotype 1b subgenomic replicon, thus being 500 times more potent than the parent nucleoside. The potency of the lead compound INX-08189 was shown to be consistent with intracellular 2'-C-methyl guanosine triphosphate levels in primary human hepatocytes. The separated diastereomers of INX-08189 were shown to have similar activity in the replicon assay and were also shown to be similar substrates for enzyme processing. INX-08189 has completed investigational new drug enabling studies and has been progressed into human clinical trials for the treatment of chronic HCV infection.
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: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Nicola
authors.initials: N
authors.lastname: Zonta
authors.forename: Stanley
authors.initials: S
authors.lastname: Chamberlain
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: Brenda
authors.initials: B
authors.lastname: Ames
authors.forename: Elena
authors.initials: E
authors.lastname: Gorovits
authors.forename: Babita
authors.initials: B
authors.lastname: Ganguly
authors.forename: Alexander
authors.initials: A
authors.lastname: Kolykhalov
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Jerry
authors.initials: J
authors.lastname: Muhammad
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Patti
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Henson
mesh_terms: D000577:Amides / Q000737:chemistry; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002478:Cells, Cultured; D015195:Drug Design; D006151:Guanosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000633:toxicity; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D010756:Phosphoric Acids / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
chemical_list: D000577:Amides; D000998:Antiviral Agents; D010756:Phosphoric Acids; D011355:Prodrugs; D006151:Guanosine; C553340:BMS-986094; D006157:Guanosine Monophosphate; C011067:phosphoramidic acid