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Antimicrobial Agents and Chemotherapy, June 2009, p. 2544-2552, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01599-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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

Stephanie T. Shi,* Koleen J. Herlihy, Joanne P. Graham, Jim Nonomiya, Sadayappan V. Rahavendran, Heather Skor, Rebecca Irvine, Susan Binford, John Tatlock, Hui Li, Javier Gonzalez, Angelica Linton, Amy K. Patick, and Cristina Lewis

Pfizer Global Research and Development, La Jolla Laboratories, 10724 Science Center Drive, San Diego, California 92121

Received 2 December 2008/ Returned for modification 23 January 2009/ Accepted 17 March 2009

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 µM against genotype 1 polymerases and a mean 50% effective concentration (EC50) of 0.075 µM 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 EC50 of 0.059 µM. PF-00868554 showed no cytotoxic effect in several human cell lines, up to the highest concentration evaluated (320 µM). 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.

* Corresponding author. Mailing address: Department of Cancer Biology, Pfizer Global Research and Development, La Jolla Laboratories, 10724 Science Center Drive, San Diego, CA 92121. Phone: (858) 526-4906. Fax: (858) 526-4349. E-mail: stephanie.shi{at}pfizer.com

{triangledown} Published ahead of print on 23 March 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, June 2009, p. 2544-2552, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01599-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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