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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cited_by cdi_FETCH-LOGICAL-a523t-41d9735e1a04b615abf5129227303ce11d7c77d04c1bc4ded8865ade730a5bf33
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container_end_page 97
container_issue 2
container_start_page 94
container_title ACS medicinal chemistry letters
container_volume 9
creator 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
description 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.
doi_str_mv 10.1021/acsmedchemlett.7b00418
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subjects Letter
title Discovery of 3,3′-Spiro[Azetidine]-2-oxo-indoline Derivatives as Fusion Inhibitors for Treatment of RSV Infection
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