title: INX-08189, a phosphoramidate prodrug of 6-O-methyl-2'-C-methyl guanosine, is a potent inhibitor of hepatitis C virus replication with excellent pharmacokinetic and pharmacodynamic properties.
abstract: INX-08189 is an aryl-phosphoramidate of 6-O-methyl-2'-C-methyl guanosine. INX-08189 was highly potent in replicon assays, with a 50% effective concentration of 10±6 nM against hepatitis C genotype 1b at 72 h. The inhibitory effect on viral replication was rapid, with a 50% effective concentration (EC50) of 35±8 nM at 24 h. An intracellular 2'-C-methyl guanosine triphosphate (2'-C-MeGTP) concentration of 2.43±0.42 pmol/10(6) cells was sufficient to achieve 90% inhibition of viral replication. In vitro resistance studies confirmed that the S282T mutation in the NS5b gene conferred an approximately 10-fold reduction in sensitivity to INX-08189. However, the complete inhibition of S282T mutant replicons still could be achieved with an EC90 of 344±170 nM. Drug combination studies of INX-08189 and ribavirin indicated significant synergy in antiviral potency both in wild-type and S282T-expressing replicons. Genotype 1b replicons could be cleared after 14 days of culture when exposed to as little as 20 nM INX-08189. No evidence of mitochondrial toxicity was observed after 14 days of INX-08189 exposure in both HepG2 and CEM human cell lines. In vivo studies of rats and cynomolgus monkeys demonstrated that 2'-C-MeGTP concentrations in liver equivalent to the EC90 could be attained after a single oral dose of INX-08189. Rat liver 2'-C-MeGTP concentrations were proportional to dose, sustained for greater than 24 h, and correlated with plasma concentrations of the nucleoside metabolite 2'-C-methyl guanosine. The characteristics displayed by INX-08189 support its continued development as a clinical candidate for the treatment of chronic HCV infection.
authors.affiliation: Inhibitex, Inc., 9005 Westside Parkway, Alpharetta, GA 30009, USA. jvernachio@inhibitex.com
authors.forename: John H
authors.initials: JH
authors.lastname: Vernachio
authors.forename: Blair
authors.initials: B
authors.lastname: Bleiman
authors.forename: K Dawn
authors.initials: KD
authors.lastname: Bryant
authors.forename: Stanley
authors.initials: S
authors.lastname: Chamberlain
authors.forename: Damound
authors.initials: D
authors.lastname: Hunley
authors.forename: Jeff
authors.initials: J
authors.lastname: Hutchins
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: Andrea
authors.initials: A
authors.lastname: Hall
authors.forename: Alexander
authors.initials: A
authors.lastname: Kolykhalov
authors.forename: Yule
authors.initials: Y
authors.lastname: Liu
authors.forename: Jerry
authors.initials: J
authors.lastname: Muhammad
authors.forename: Nicholas
authors.initials: N
authors.lastname: Raja
authors.forename: C Robin
authors.initials: CR
authors.lastname: Walters
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Karen
authors.initials: K
authors.lastname: Williams
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Patti
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Henson
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: Christopher
authors.initials: C
authors.lastname: McGuigan
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D006151:Guanosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D010756:Phosphoric Acids / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000577:Amides; D000998:Antiviral Agents; D010756:Phosphoric Acids; D011355:Prodrugs; D006151:Guanosine; C011067:phosphoramidic acid