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
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.
