Preclinical Characterization of PF-00868554, a Potent Nonnucleoside Inhibitor of the Hepatitis C Virus RNA-Dependent RNA Polymerase

Department of Cancer Biology, Pfizer Global Research and Development, La Jolla Laboratories, 10724 Science Center Drive, San Diego, CA 92121, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 04/2009; 53(6):2544-52. DOI: 10.1128/AAC.01599-08
Source: PubMed


PF-00868554 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase, which exerts its inhibitory effect by binding to the thumb base domain of the protein. It is a potent and selective inhibitor, with a mean 50% inhibitory concentration of 0.019 microM against genotype 1 polymerases and a mean 50% effective concentration (EC(50)) of 0.075 microM against the genotype 1b-Con1 replicon. To determine the in vitro antiviral activity of PF-00868554 against various HCV strains, a panel of chimeric replicons was generated, in which polymerase sequences derived from genotype 1a and 1b clinical isolates were cloned into the 1b-Con1 subgenomic reporter replicon. Our results indicate that PF-00868554 has potent in vitro antiviral activity against a majority (95.8%) of genotype 1a and 1b replicons, with an overall mean EC(50) of 0.059 microM. PF-00868554 showed no cytotoxic effect in several human cell lines, up to the highest concentration evaluated (320 microM). Furthermore, the antiviral activity of PF-00868554 was retained in the presence of human serum proteins. An in vitro resistance study of PF-00868554 identified M423T as the predominant resistance mutation, resulting in a 761-fold reduction in susceptibility to PF-00868554 but no change in susceptibility to alpha interferon and a polymerase inhibitor that binds to a different region. PF-00868554 also showed good pharmacokinetic properties in preclinical animal species. Our results demonstrate that PF-00868554 has potent and broad-spectrum antiviral activity against genotype 1 HCV strains, supporting its use as an oral antiviral agent in HCV-infected patients.

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Available from: M. Angelica Linton, Apr 15, 2015
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    • "utation , resulting in a 761 - fold reduction in susceptibility to filibuvir , but no change in susceptibility to IFN - α and a polymerase inhibitor that binds to a different region . Filibuvir also showed good pharmacokinetic properties in preclinical animal species , revealing promising oral bioavailability in both rodent and nonrodent species ( Shi et al . , 2009 ) . Also , filibuvir seemed not to affect any of the major CYP isoforms ( IC 50 >30 µmol / L for 1A2 , 2C8 , 2D6 , 3A4 , 2C9 , and 2C19 ) ( Li et al . , 2009 ) ."
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