Discovery of Phenylaminopyridine Derivatives as Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

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• 作者：Junwon Kim ; Doohyun Lee ; Changmin Park ; Wonyoung So ; Mina Jo ; Taedong Ok ; Jeongjin Kwon ; Sunju Kong ; Suyeon Jo ; Youngmi Kim ; Jihyun Choi ; Hyoung Cheul Kim ; Yoonae Ko ; Inhee Choi ; Youngsam Park ; Jaewan Yoon ; Moon Kyeong Ju ; Junghwan Kim ; Sung-Jun Han ; Tae-Hee Kim ; Jonathan Cechetto ; Jiyoun Nam ; Peter Sommer ; Michel Liuzzi ; Jinhwa Lee ; Zaesung No
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：August 9, 2012
• 年：2012
• 卷：3
• 期：8
• 页码：678-682
• 全文大小：306K
• 年卷期：v.3,no.8(August 9, 2012)
• ISSN：1948-5875

文摘

We identified a novel class of aryl-substituted triazine compounds as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) during a high-throughput screening campaign that evaluated more than 200000 compounds for antihuman immunodeficiency virus (HIV) activity using a cell-based full replication assay. Herein, we disclose the optimization of the antiviral activity in a cell-based assay system leading to the discovery of compound 27, which possessed excellent potency against wild-type HIV-1 (EC₅₀ = 0.2 nM) as well as viruses bearing Y181C and K103N resistance mutations in the reverse transcriptase gene. The X-ray crystal structure of compound 27 complexed with wild-type reverse transcriptase confirmed the mode of action of this novel class of NNRTIs. Introduction of a chloro functional group in the pyrazole moiety dramatically improved hERG and CYP inhibition profiles, yielding highly promising leads for further development.

Keywords:

HIV-1; reverse transcriptase; non-nucleoside reverse transcriptase inhibitors; synthesis; X-ray crystal structure