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 Thommes; Elizabeth 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

doi:10.1021/jm400317w

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 Thommes

Elizabeth 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

Research output: Contribution to journal › Article › peer-review

48 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 language	English
Journal	Journal of Medicinal Chemistry
Early online date	14 May 2013
DOIs	https://doi.org/10.1021/jm400317w
Publication status	Early online date - 14 May 2013

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10.1021/jm400317w

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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. Advance online publication. https://doi.org/10.1021/jm400317w

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title = "Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase",

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.",

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

year = "2013",

month = may,

day = "14",

doi = "10.1021/jm400317w",

language = "English",

journal = "Journal of Medicinal Chemistry",

publisher = "American Chemical Society",

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Maynard, A, Crosby, RM, Ellis, B, Hamatake, R, Hong, Z, Johns, BA, Kahler, KM, Koble, C, Leivers, AL, Leivers, MR, Mathis, A, Peat, AJ, Pouliot, JJ, Roberts, CD, Samano, V, Schmidt, RM, Smith, GK, Spaltenstein, A, Stewart, EL, Thommes, P, Turner, EM, Voitenleitner, C, Walker, JT, Waitt, G, Weatherhead, J, Weaver, KL, Williams, S, Wright, L, Xiong, ZZ, Haigh, D & Shotwell, JB 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

TY - JOUR

T1 - Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase

AU - Maynard, Andrew

AU - Crosby, Renae M

AU - Ellis, Byron

AU - Hamatake, Robert

AU - Hong, Zhi

AU - Johns, Brian A

AU - Kahler, Kirsten M

AU - Koble, Cecilia

AU - Leivers, Anna L

AU - Leivers, Martin R

AU - Mathis, Amanda

AU - Peat, Andrew J

AU - Pouliot, Jeffrey J

AU - Roberts, Christopher D

AU - Samano, Vicente

AU - Schmidt, Rachel M

AU - Smith, Gary K

AU - Spaltenstein, Andrew

AU - Stewart, Eugene L

AU - Thommes, Pia

AU - Turner, Elizabeth M

AU - Voitenleitner, Christian

AU - Walker, Jill T

AU - Waitt, Greg

AU - Weatherhead, Jason

AU - Weaver, Kurt L

AU - Williams, Shawn

AU - Wright, Lois

AU - Xiong, Zhiping Z

AU - Haigh, David

AU - Shotwell, J Brad

PY - 2013/5/14

Y1 - 2013/5/14

N2 - 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.

AB - 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.

U2 - 10.1021/jm400317w

DO - 10.1021/jm400317w

M3 - Article

C2 - 23672667

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

ER -

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

Abstract

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