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

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• 作者：Andrew Maynard ; Renae M. Crosby ; Byron Ellis ; Robert Hamatake ; Zhi Hong ; Brian A. Johns ; Kirsten M. Kahler ; Cecilia Koble ; Anna 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 Thommes ; Elizabeth M. Turner ; Christian Voitenleitner ; Jill T. Walker ; Greg Waitt ; Jason Weatherhead ; Kurt Weaver ; Shawn Williams ; Lois Wright ; Zhiping Z. Xiong ; David Haigh ; J. Brad Shotwell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：1902-1913
• 全文大小：667K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

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鈥揳ctivity relationships associated with inhibition of HCV replication in a subgenomic 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 3 (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.