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.
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Authors | John H Vernachio, Blair Bleiman, K Dawn Bryant, Stanley Chamberlain, Damound Hunley, Jeff Hutchins, Brenda Ames, Elena Gorovits, Babita Ganguly, Andrea Hall, Alexander Kolykhalov, Yule Liu, Jerry Muhammad, Nicholas Raja, C Robin Walters, Jin Wang, Karen Williams, Joseph M Patti, Geoffrey Henson, Karolina Madela, Mohamed Aljarah, Arnaud Gilles, Christopher McGuigan |
Journal | Antimicrobial agents and chemotherapy
(Antimicrob Agents Chemother)
Vol. 55
Issue 5
Pg. 1843-51
(May 2011)
ISSN: 1098-6596 [Electronic] United States |
PMID | 21357300
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amides
- Antiviral Agents
- Phosphoric Acids
- Prodrugs
- Guanosine
- phosphoramidic acid
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Topics |
- Amides
(chemistry)
- Animals
- Antiviral Agents
(pharmacokinetics, pharmacology)
- Cell Line
- Cell Line, Tumor
- Guanosine
(analogs & derivatives, chemistry, pharmacokinetics, pharmacology)
- Hepacivirus
(drug effects)
- Humans
- Macaca fascicularis
- Male
- Phosphoric Acids
(chemistry)
- Prodrugs
(chemistry, pharmacokinetics, pharmacology)
- Rats
- Rats, Sprague-Dawley
- Virus Replication
(drug effects)
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