1. Discovery of Phenylaminopyridine Derivatives as Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors
- Author
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Young-Mi Kim, Sunju Kong, Jeongjin Kwon, Youngsam Park, Jonathan Cechetto, Jihyun Choi, Zaesung No, Taedong Ok, Wonyoung So, Hyoung Cheul Kim, Moon Kyeong Ju, Suyeon Jo, Tae-Hee Kim, Jiyoun Nam, Mina Jo, Changmin Park, Inhee Choi, Michel Liuzzi, Sung-Jun Han, Jinhwa Lee, Junwon Kim, Doohyun Lee, Jaewan Yoon, Peter Sommer, Junghwan Kim, and Yoonae Ko
- Subjects
biology ,Organic Chemistry ,Cell ,hERG ,virus diseases ,Pyrazole ,Biochemistry ,Virology ,Reverse transcriptase ,Nucleoside Reverse Transcriptase Inhibitor ,chemistry.chemical_compound ,Discovery and development of non-nucleoside reverse-transcriptase inhibitors ,medicine.anatomical_structure ,chemistry ,Drug Discovery ,medicine ,biology.protein ,Moiety ,Triazine - Abstract
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.
- Published
- 2012