Inhibitors of Hepatitis C Virus Polymerase: Synthesis and Biological Characterization of Unsymmetrical Dialkyl-Hydroxynaphthalenoyl-benzothiadiazines

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• 作者：Rolf Wagner* ; Daniel P. Larson* ; David W. A. Beno ; Todd D. Bosse ; John F. Darbyshire^† ; ; Yi Gao ; Bradley D. Gates ; Wenping He^‡ ; ; Rodger F. Henry ; Lisa E. Hernandez ; Doug
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：March 26, 2009
• 年：2009
• 卷：52
• 期：6
• 页码：1659-1669
• 全文大小：187K
• 年卷期：v.52,no.6(March 26, 2009)
• ISSN：1520-4804

文摘

The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and has been a prime target for drug discovery research. Our efforts directed toward the discovery of HCV polymerase inhibitors resulted in the identification of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines 2 and 3. The most active compound displayed activity in genotypes 1a and 1b polymerase and replicon cell culture inhibition assays at subnanomolar and low nanomolar concentrations, respectively. It also displayed an excellent pharmacokinetic profile in rats, with a plasma elimination half-life after intravenous dosing of 4.5 h, oral bioavailability of 77%, and a peak liver concentration of 21.8 μg/mL.