Discovery of novel tricyclic indole derived inhibitors of HCV NS5B RNA dependent RNA polymerase

• Published in: Bioorganic & medicinal chemistry Vol. 21; no. 7; pp. 2007 - 2017
• Main Authors: Venkatraman, Srikanth, Velazquez, Francisco, Gavalas, Stephen, Wu, Wanli, Chen, Kevin X., Nair, Anilkumar G., Bennett, Frank, Huang, Yuhua, Pinto, Patrick, Jiang, Yueheng, Selyutin, Oleg, Vibulbhan, Bancha, Zeng, Qingbei, Lesburg, Charles, Duca, Jose, Huang, Hsueh-Cheng, Agrawal, Sony, Jiang, Chuan-kui, Ferrari, Eric, Li, Cheng, Kozlowski, Joseph, Rosenblum, Stuart, Shih, Neng-Yang, Njoroge, F. George
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-04-2013
• Subjects: Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Binding Sites; Crystal structure; Crystallography, X-Ray; DNA-directed RNA polymerase; genome; HCV; Hepacivirus - chemistry; Hepacivirus - enzymology; hepatitis C; Hepatitis C - drug therapy; Hepatitis C - virology; Hepatitis C virus; Humans; Indoles - chemistry; Indoles - pharmacology; Molecular Docking Simulation; NS5B; proteins; Pyridone; Replicon; RNA; RNA Replicase - antagonists & inhibitors; RNA Replicase - chemistry; RNA Replicase - metabolism; Structure-Activity Relationship; structure-activity relationships; Tricyclic Indole; X-ray diffraction; Tricyclic Indole; HCV; Pyridone; NS5B; Replicon
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.01.024

The characterization of HCV genome has identified various vital functional proteins involved in the life cycle of hepatitis C virus. This has resulted in many novel enzymatic targets that are potential for development of therapeutic agents. The HCV RNA dependent RNA polymerase (HCV NS5B) is one such essential enzyme for HCV replication that has been well characterized and studied by various groups to develop novel therapies for hepatitis C. In this paper, we describe our efforts towards the identification and structure–activity relationship (SAR) of novel tricyclic indole derivatives that bind close to the palm site of the NS5B polymerase. X-ray crystal structure of an inhibitor bound to the polymerase is also described.