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2
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Discovery of methylsulfonyl indazoles as potent and orally active respiratory syncytial Virus(RSV) fusion inhibitors.发现甲基磺酰吲哚作为有效的、口服活性的呼吸道合胞病毒（RSV）融合抑制剂。
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本文引用的文献

1
Discovery of methylsulfonyl indazoles as potent and orally active respiratory syncytial Virus(RSV) fusion inhibitors.发现甲基磺酰吲哚作为有效的、口服活性的呼吸道合胞病毒（RSV）融合抑制剂。
Eur J Med Chem. 2017 Sep 29;138:1147-1157. doi: 10.1016/j.ejmech.2017.07.032. Epub 2017 Jul 20.
2
Discovery of imidazopyridine derivatives as highly potent respiratory syncytial virus fusion inhibitors.发现咪唑并吡啶衍生物作为高效呼吸道合胞病毒融合抑制剂
ACS Med Chem Lett. 2015 Jan 25;6(3):359-62. doi: 10.1021/acsmedchemlett.5b00008. eCollection 2015 Mar 12.
3
Discovery of an oral respiratory syncytial virus (RSV) fusion inhibitor (GS-5806) and clinical proof of concept in a human RSV challenge study.发现一种口服呼吸道合胞病毒（RSV）融合抑制剂（GS-5806），并在人体 RSV 挑战研究中得到临床概念验证。
J Med Chem. 2015 Feb 26;58(4):1630-43. doi: 10.1021/jm5017768. Epub 2015 Jan 27.
4
Oral GS-5806 activity in a respiratory syncytial virus challenge study.呼吸道合胞病毒挑战研究中口服 GS-5806 的活性。
N Engl J Med. 2014 Aug 21;371(8):711-22. doi: 10.1056/NEJMoa1401184.
5
Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis.全球儿童因呼吸道合胞病毒导致的急性下呼吸道感染负担：系统评价和荟萃分析。
Lancet. 2010 May 1;375(9725):1545-55. doi: 10.1016/S0140-6736(10)60206-1.
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Respiratory syncytial virus market.呼吸道合胞病毒市场。
Nat Rev Drug Discov. 2010 Jan;9(1):15-6. doi: 10.1038/nrd3075.
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The burden of respiratory syncytial virus infection in young children.幼儿呼吸道合胞病毒感染的负担
N Engl J Med. 2009 Feb 5;360(6):588-98. doi: 10.1056/NEJMoa0804877.
8
Effect of cathepsin K inhibitors on bone resorption.组织蛋白酶K抑制剂对骨吸收的作用。
J Med Chem. 2008 Sep 11;51(17):5459-62. doi: 10.1021/jm800626a. Epub 2008 Aug 16.
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Discovery of a new class of potent, selective, and orally bioavailable CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases.发现一类新型强效、选择性且口服生物可利用的CRTH2（DP2）受体拮抗剂，用于治疗过敏性炎症性疾病。
J Med Chem. 2008 Apr 10;51(7):2227-43. doi: 10.1021/jm701383e. Epub 2008 Mar 5.
10
Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121).呼吸道合胞病毒融合抑制剂临床候选药物的筛选。2. 吗啉基丙氨基苯并咪唑衍生物（TMC353121）的发现。
J Med Chem. 2008 Feb 28;51(4):875-96. doi: 10.1021/jm701284j. Epub 2008 Feb 7.

发现3,3'-螺[氮杂环丁烷]-2-氧代吲哚啉衍生物作为治疗呼吸道合胞病毒感染的融合抑制剂

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

作者信息

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

机构信息

WuXi AppTec (Shanghai) Co., Ltd, 288 FuTe Zhong Road, Shanghai 200131, P. R. China.

Buchang Pharmaceutical, 50 Gaoxin Road, Gaoxin District, Xi'an 710075, Shanxi Province, P. R. China.

出版信息

ACS Med Chem Lett. 2018 Jan 10;9(2):94-97. doi: 10.1021/acsmedchemlett.7b00418. eCollection 2018 Feb 8.

DOI:10.1021/acsmedchemlett.7b00418
PMID:29456794
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5807868/
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 , which exhibited excellent potency with an EC value of 0.8 nM and demonstrated 71% oral bioavailability in mice. In a mouse challenge model of RVS infection, demonstrated superior efficacy with a 3.9log RSV virus load reduction in the lung following an oral dose of 50 mg/kg.

摘要

合成了一系列新的3,3'-螺环-2-氧代吲哚啉衍生物，并在基于细胞的试验和动物模型中对呼吸道合胞病毒（RSV）进行了评估。广泛的构效关系研究产生了一个先导化合物，其表现出优异的效力，EC值为0.8 nM，在小鼠中显示出71%的口服生物利用度。在RSV感染的小鼠攻毒模型中，口服50 mg/kg剂量后，肺部RSV病毒载量降低了3.9个对数，显示出优异的疗效。