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

被引：48

作者：

Chong, Pek ^{[1
]}

Sebahar, Paul ^{[1
]}

Youngman, Michael ^{[1
]}

Garrido, Dulce ^{[1
]}

Zhang, Huichang ^{[1
]}

Stewart, Eugene L. ^{[1
]}

Nolte, Robert T. ^{[1
]}

Wang, Liping ^{[1
]}

Ferris, Robert G. ^{[1
]}

Edelstein, Mark ^{[1
]}

Weaver, Kurt ^{[1
]}

Mathis, Amanda ^{[1
]}

Peat, Andrew ^{[1
]}

机构：

[1] GlaxoSmithKline Res & Dev Ltd, Res Triangle Pk, NC 27709 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 23期

关键词：

WILD-TYPE; DISPOSITION; IMIDAZOLES; METABOLISM; DISCOVERY; RESISTANT; MUTANT; NNRTI;

D O I：

10.1021/jm301294g

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：10601 / 10609

页数：9

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