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

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.

SUBMITTER: Eastman KJ

PROVIDER: S-EPMC6072320 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Eastman Kyle J KJ Parcella Kyle K Yeung Kap-Sun KS Grant-Young Katharine A KA Zhu Juliang J Wang Tao T Zhang Zhongxing Z Yin Zhiwei Z Beno Brett R BR Sheriff Steven S Kish Kevin K Tredup Jeffrey J Jardel Adam G AG Halan Vivek V Ghosh Kaushik K Parker Dawn D Mosure Kathy K Fang Hua H Wang Ying-Kai YK Lemm Julie J Zhuo Xiaoliang X Hanumegowda Umesh U Rigat Karen K Donoso Maria M Tuttle Maria M Zvyaga Tatyana T Haarhoff Zuzana Z Meanwell Nicholas A NA Soars Matthew G MG Roberts Susan B SB Kadow John F JF

MedChemComm 20170208 4

The development of a series of novel 7-azabenzofurans exhibiting pan-genotype inhibition of HCV NS5B polymerase <i>via</i> 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 (<b>43</b>) as a preclinical candidate. ...[more]

PMID: 30108798

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