The discovery of a pan-genotypic, primer grip inhibitor of HCV NS5B polymerase

Kyle J. Eastman; Kyle Parcella; Kap-Sun Yeung; Katharine A. Grant-Young; Juliang Zhu; Tao Wang; Zhongxing Zhang; Zhiwei Yin; Brett R. Beno; Steven Sheriff; Kevin Kish; Jeffrey Tredup; Adam G. Jardel; Vivek Halan; Kaushik Ghosh; Dawn Parker; Kathy Mosure; Hua Fang; Ying-Kai Wang; Julie Lemm; Xiaoliang Zhuo; Umesh Hanumegowda; Karen Rigat; Maria Donoso; Maria Tuttle; Tatyana Zvyaga; Zuzana Haarhoff; Nicholas A. Meanwell; Matthew G. Soars; Susan B. Roberts; John F. Kadow

doi:10.1039/C6MD00636A

The discovery of a pan-genotypic, primer grip inhibitor of HCV NS5B polymerase†‡

Kyle J. Eastman,

*^a Kyle Parcella,^a Kap-Sun Yeung,^a Katharine A. Grant-Young,^a Juliang Zhu,^a Tao Wang,^a Zhongxing Zhang,^a Zhiwei Yin,^a Brett R. Beno,^a Steven Sheriff,^a Kevin Kish,^a Jeffrey Tredup,^a Adam G. Jardel,^a Vivek Halan,^a Kaushik Ghosh,^a Dawn Parker,^a Kathy Mosure,^a Hua Fang,^a Ying-Kai Wang,^a Julie Lemm,^a Xiaoliang Zhuo,^a Umesh Hanumegowda,^a Karen Rigat,^a Maria Donoso,^a Maria Tuttle,^a Tatyana Zvyaga,^a Zuzana Haarhoff,^a Nicholas A. Meanwell,^a Matthew G. Soars,^a Susan B. Roberts^a and John F. Kadow^a

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* Corresponding authors

^a Bristol-Myers Squibb Pharmaceutical Research and Development, Department of Discovery Chemistry and Molecular Technologies, 5 Research Parkway, Wallingford, Connecticut, USA
E-mail: kyle.eastman@bms.com

Abstract

The development of a series of novel 7-azabenzofurans exhibiting pan-genotype inhibition of HCV NS5B polymerase via binding to the primer grip site is presented. Many challenges, including poor oral bioavailability, high clearance, bioactivation, high human serum shift, and metabolic stability were encountered and overcome through SAR studies. This work culminated in the selection of BMS-986139 (43) as a preclinical candidate.

MedChemComm

The discovery of a pan-genotypic, primer grip inhibitor of HCV NS5B polymerase†‡

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The discovery of a pan-genotypic, primer grip inhibitor of HCV NS5B polymerase

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