Discovery of 3,3′-Spiro[Azetidine]-2-oxo-indoline Derivatives as Fusion Inhibitors for Treatment of RSV Infection

A new series of 3,3′-spirocyclic-2-oxo-indoline derivatives was synthesized and evaluated against respiratory syncytial virus (RSV) in a cell-based assay and animal model. Extensive structure–activity relationship study led to a lead compound 14h, which exhibited excellent in vitro potency with an E...

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Published in:ACS medicinal chemistry letters 2018-02, Vol.9 (2), p.94-97
Main Authors: Shi, Weihua, Jiang, Zhigan, He, Haiying, Xiao, Fubiao, Lin, Fusen, Sun, Ya, Hou, Lijuan, Shen, Liang, Han, Lixia, Zeng, Minggao, Lai, Kunmin, Gu, Zhengxian, Chen, Xinsheng, Zhao, Tao, Guo, Li, Yang, Chun, Li, Jian, Chen, Shuhui
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Language:English
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Letter
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Summary:A new series of 3,3′-spirocyclic-2-oxo-indoline derivatives was synthesized and evaluated against respiratory syncytial virus (RSV) in a cell-based assay and animal model. Extensive structure–activity relationship study led to a lead compound 14h, which exhibited excellent in vitro potency with an EC50 value of 0.8 nM and demonstrated 71% oral bioavailability in mice. In a mouse challenge model of RVS infection, 14h demonstrated superior efficacy with a 3.9log RSV virus load reduction in the lung following an oral dose of 50 mg/kg.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.7b00418