Rational Design of Potent Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase

详细信息    查看全文

• 作者：Pek Chong ; Paul Sebahar ; Michael Youngman ; Dulce Garrido ; Huichang Zhang ; Eugene L. Stewart ; Robert T. Nolte ; Liping Wang ; Robert G. Ferris ; Mark Edelstein ; Kurt Weaver ; Amanda Mathis ; Andrew Peat
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：55
• 期：23
• 页码：10601-10609
• 全文大小：515K
• 年卷期：v.55,no.23(December 13, 2012)
• ISSN：1520-4804

文摘

A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC₅₀ < 1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.