Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase

Andrew Maynard, Renae M Crosby, Byron Ellis, Robert Hamatake, Zhi Hong, Brian A Johns, Kirsten M Kahler, Cecilia Koble, Anna L Leivers, Martin R Leivers, Amanda Mathis, Andrew J Peat, Jeffrey J Pouliot, Christopher D Roberts, Vicente Samano, Rachel M Schmidt, Gary K Smith, Andrew Spaltenstein, Eugene L Stewart, Pia ThommesElizabeth M Turner, Christian Voitenleitner, Jill T Walker, Greg Waitt, Jason Weatherhead, Kurt L Weaver, Shawn Williams, Lois Wright, Zhiping Z Xiong, David Haigh, J Brad Shotwell

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29 Citations (Scopus)

Abstract

A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a sub-genomic replication system for a series of non-nucleoside boron-containing HCV RNA-Dependent RNA Polymerase (NS5B) inhibitors are described. A summary of the discovery of GSK5852 (3), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Early online date14 May 2013
DOIs
Publication statusEarly online date - 14 May 2013

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    Maynard, A., Crosby, R. M., Ellis, B., Hamatake, R., Hong, Z., Johns, B. A., Kahler, K. M., Koble, C., Leivers, A. L., Leivers, M. R., Mathis, A., Peat, A. J., Pouliot, J. J., Roberts, C. D., Samano, V., Schmidt, R. M., Smith, G. K., Spaltenstein, A., Stewart, E. L., ... Shotwell, J. B. (2013). Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase. Journal of Medicinal Chemistry. https://doi.org/10.1021/jm400317w