Discovery of potent macrocyclic HCV NS5A inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2016-08, Vol.26 (15), p.3793-3799
• Main Authors: Yu, Wensheng, Vibulbhan, Bancha, Rosenblum, Stuart B., Martin, Gregory S., Vellekoop, A. Samuel, Holst, Christian L., Coburn, Craig A., Wong, Michael, Selyutin, Oleg, Ji, Tao, Zhong, Bin, Hu, Bin, Chen, Lei, Dwyer, Michael P., Jiang, Yueheng, Nair, Anilkumar G., Tong, Ling, Zeng, Qingbei, Agrawal, Sony, Carr, Donna, Rokosz, Laura, Liu, Rong, Curry, Stephanie, McMonagle, Patricia, Ingravallo, Paul, Lahser, Fred, Asante-Appiah, Ernest, Fells, James, Kozlowski, Joseph A.
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; DAA; Dose-Response Relationship, Drug; Drug Discovery; HCV infection; HCV NS5A inhibitor; Hepacivirus - drug effects; Hepatitis C - drug therapy; Hepatitis C virus; Heterocyclic Compounds, 4 or More Rings - chemical synthesis; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacology; Macrocycle; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; Microbial Sensitivity Tests; MK-4882; MK-8325; Molecular Structure; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors; Virus Replication - drug effects
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.05.042

[Display omitted] HCV NS5A inhibitors have demonstrated impressive in vitro virologic profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed-dose combination (FDC) regimen for the treatment of HCV infection. Merck’s effort in this area identified MK-4882 and MK-8325 as early development leads. Herein, we describe the discovery of potent macrocyclic NS5A inhibitors bearing the MK-8325 or MK-4882 core structure.