Discovery of β-D-2′-deoxy-2′-α-fluoro-4′-α-cyano-5-aza-7,9-dideaza adenosine as a potent nucleoside inhibitor of respiratory syncytial virus with excellent selectivity over mitochondrial RNA and DNA polymerases

被引：23

作者：

Clarke, Michael O. ^{[1
]}

Mackman, Richard ^{[1
]}

Byun, Daniel ^{[1
]}

Hui, Hon ^{[1
]}

Barauskas, Ona ^{[1
]}

Birkus, Gabriel ^{[1
]}

Chun, Byoung-Kwon ^{[1
]}

Doerffler, Edward ^{[1
]}

Feng, Joy ^{[1
]}

Karki, Kapil ^{[1
]}

Lee, Gary ^{[1
]}

Perron, Michel ^{[1
]}

Siegel, Dustin ^{[1
]}

Swaminathan, Swami ^{[1
]}

Lee, William ^{[1
]}

机构：

[1] Gilead Sci Inc, Foster City, CA 94404 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 12期

关键词：

Nucleoside; Respiratory syncytial virus; Mitochondria; DNA polymerase gamma; Mitochondrial RNA polymerase; INFLUENZA-B VIRUSES; 2'-DEOXY-2'-FLUORORIBOSIDES; INFECTION; TOXICITY; TRIAL;

D O I：

10.1016/j.bmcl.2015.04.073

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Novel 4'-substituted beta-D-2'-deoxy-2'-alpha-fluoro (2'd2'F) nucleoside inhibitors of respiratory syncytial virus (RSV) are reported. The introduction of 4'-substitution onto 2'd2'F nucleoside analogs resulted in compounds demonstrating potent cell based RSV inhibition, improved inhibition of the RSV polymerase by the nucleoside triphosphate metabolites, and enhanced selectivity over incorporation by mitochondrial RNA and DNA polymerases. Selectivity over the mitochondrial polymerases was found to be extremely sensitive to the specific 4'-substitution and not readily predictable. Combining the most potent and selective 4'-groups from N-nucleoside analogs onto a 2'd2'F C-nucleoside analog resulted in the identification of beta-D-2'-deoxy-2'-alpha-fluoro-4'-alpha-cyano-5-aza-7,9-dideaza adenosine as a promising nucleoside lead for RSV. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：2484 / 2487

页数：4

共 21 条

[1]

Ahmad T., 2014, HEPATOLOGY, DOI 10.1002

[2] Sensitivity of Mitochondrial Transcription and Resistance of RNA Polymerase II Dependent Nuclear Transcription to Antiviral Ribonucleosides [J].

Arnold, Jamie J. ;

Sharma, Suresh D. ;

Feng, Joy Y. ;

Ray, Adrian S. ;

Smidansky, Eric D. ;

Kireeva, Maria L. ;

Cho, Aesop ;

Perry, Jason ;

Vela, Jennifer E. ;

Park, Yeojin ;

Xu, Yili ;

Tian, Yang ;

Babusis, Darius ;

Barauskus, Ona ;

Peterson, Blake R. ;

Gnatt, Averell ;

Kashlev, Mikhail ;

Zhong, Weidong ;

Cameron, Craig E. .

PLOS PATHOGENS, 2012, 8 (11)

[3]

Beigelman L., International Patent Application, Patent No. [PCT/ US2012/ 071063, 2012071063]

[4]

Beigelman L., 2013, Preparation of amino acid-substituted nucleosides, nucleotides and analogs as antiviral agents, Patent No. [WO Patent 2013096679, 2013096679, WO/ 2013/ 096679]

[5] Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients [J].