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

Vernachio, John H., Bleiman, Blair, Bryant, K. Dawn, Chamberlain, Stanley, Hunley, Damound, Hutchins, Jeff, Ames, Brenda, Gorovits, Elena, Ganguly, Babita, Hall, Andrea, Kolykhalov, Alexander, Liu, Yule, Muhammad, Jerry, Raja, Nicholas, Walters, C. Robin, Wang, Jin, Williams, Karen, Patti, Joseph M., Henson, Geoffrey, Madela, Karolina, Aljarah, Mohamed, Gilles, Arnaud and McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X 2011. 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. Antimicrobial Agents and Chemotherapy 55 (5) , pp. 1843-1851. 10.1128/AAC.01335-10

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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/106 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > RS Pharmacy and materia medica
Publisher:	American Society for Microbiology
ISSN:	0066-4804
Related URLs:	Publisher
Last Modified:	06 May 2023 09:25
URI:	https://orca.cardiff.ac.uk/id/eprint/6987

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