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

ABSTRACT: 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.

SUBMITTER: Shi W

PROVIDER: S-EPMC5807868 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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

Shi Weihua W Jiang Zhigan Z He Haiying H Xiao Fubiao F Lin Fusen F Sun Ya Y Hou Lijuan L Shen Liang L Han Lixia L Zeng Minggao M Lai Kunmin K Gu Zhengxian Z Chen Xinsheng X Zhao Tao T Guo Li L Yang Chun C Li Jian J Chen Shuhui S

ACS medicinal chemistry letters 20180110 2

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 ...[more]

PMID: 29456794

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