Hepatitis C Replication Inhibitors That Target the Viral NS4B Protein

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• 作者：John F. Miller ; Pek Y. Chong ; J. Brad Shotwell ; John G. Catalano ; Vincent W.-F. Tai ; Jing Fang ; Anna L. Banka ; Christopher D. Roberts ; Michael Youngman ; Huichang Zhang ; Zhiping Xiong ; Amanda Mathis ; Jeffery J. Pouliot ; Robert K. Hamatake ; Daniel J. Price ; John W. Seal ; III ; Lisa L. Stroup ; Katrina L. Creech ; Luz H. Carballo ; Dan Todd ; Andrew Spaltenstein ; Sylvia Furst ; Zhi Hong ; Andrew J. Peat
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：2107-2120
• 全文大小：547K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound 1a was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric 鈥渉umanized鈥?mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.