Conformation-Based Restrictions and Scaffold Replacements in the Design of Hepatitis C Virus Polymerase Inhibitors: Discovery of Deleobuvir (BI 207127)

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• 作者：Steven R. LaPlante ; Michael B枚s ; Christian Brochu ; Catherine Chabot ; Ren茅 Coulombe ; James R. Gillard ; Araz Jakalian ; Martin Poirier ; Jean Rancourt ; Timothy Stammers ; Bounkham Thavonekham ; Pierre L. Beaulieu ; George Kukolj ; Youla S. Tsantrizos
• 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：1845-1854
• 全文大小：548K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

Conformational restrictions of flexible torsion angles were used to guide the identification of new chemotypes of HCV NS5B inhibitors. Sites for rigidification were based on an acquired conformational understanding of compound binding requirements and the roles of substituents in the free and bound states. Chemical bioisosteres of amide bonds were explored to improve cell-based potency. Examples are shown, including the design concept that led to the discovery of the phase III clinical candidate deleobuvir (BI 207127). The structure-based strategies employed have general utility in drug design.