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

详细信息    查看全文

• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 12, 2012
• 年：2012
• 卷：55
• 期：7
• 页码：3021-3026
• 全文大小：320K
• 年卷期：v.55,no.7(April 12, 2012)
• ISSN：1520-4804

文摘

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.