Discovery of Novel Urea-Based
Hepatitis C Protease
Inhibitors with High Potency against Protease-Inhibitor-Resistant
Mutants

Kazmierski, Wieslaw M.; Hamatake, Robert; Duan, Maosheng; Wright, Lois L.; Smith, Gary K.; Jarvest, Richard
L.; Ji, Jing-Jing; Cooper, Joel P.; Tallant, Matthew D.; Crosby, Renae M.; Creech, Katrina; Wang, Amy; Li, Xianfeng; Zhang, Suoming; Zhang, Yong-Kang; Liu, Yang; Ding, Charles Z.; Zhou, Yasheen; Plattner, Jacob J.; Baker, Stephen J.; Bu, Wei; Liu, Liang

doi:10.1021/jm201278q.s001

jm201278q_si_001.pdf (280.14 kB)

Discovery of Novel Urea-Based Hepatitis C Protease Inhibitors with High Potency against Protease-Inhibitor-Resistant Mutants

journal contribution

posted on 2016-02-21, 14:38 authored by Wieslaw M. Kazmierski, Robert Hamatake, Maosheng Duan, Lois L. Wright, Gary K. Smith, Richard L. Jarvest, Jing-Jing Ji, Joel P. Cooper, Matthew D. Tallant, Renae M. Crosby, Katrina Creech, Amy Wang, Xianfeng Li, Suoming Zhang, Yong-Kang Zhang, Yang Liu, Charles Z. Ding, Yasheen Zhou, Jacob J. Plattner, Stephen J. Baker, Wei Bu, Liang Liu

The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.