与丙型肝炎NS4B直接相互作用的咪唑并[1,2 - a]吡啶：初步临床前特征研究
Imidazo[1,2-a]pyridines That Directly Interact with Hepatitis C NS4B: Initial Preclinical Characterization.
作者信息
Shotwell J Brad, Baskaran Subramanian, Chong Pek, Creech Katrina L, Crosby Renae M, Dickson Hamilton, Fang Jing, Garrido Dulce, Mathis Amanda, Maung Jack, Parks Derek J, Pouliot Jeffrey J, Price Daniel J, Rai Roopa, Seal John W, Schmitz Uli, Tai Vincent W F, Thomson Michael, Xie Mi, Xiong Zhiping Z, Peat Andrew J
机构信息
GlaxoSmithKline , Antiviral Discovery Performance Unit, 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
GlaxoSmithKline , Platform Technology and Science, 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
出版信息
ACS Med Chem Lett. 2012 May 24;3(7):565-9. doi: 10.1021/ml300090x. eCollection 2012 Jul 12.
Abstract
A series of imidazo[1,2-a]pyridines which directly bind to HCV Non-Structural Protein 4B (NS4B) is described. This series demonstrates potent in vitro inhibition of HCV replication (EC50 < 10 nM), direct binding to purified NS4B protein (IC50 < 20 nM), and an HCV resistance pattern associated with NS4B (H94N/R, V105L/M, F98L) that are unique among reported HCV clinical assets, suggestive of the potential for additive or synergistic combination with other small molecule inhibitors of HCV replication.
摘要
描述了一系列直接与丙型肝炎病毒非结构蛋白4B（NS4B）结合的咪唑并[1,2-a]吡啶。该系列在体外表现出对丙型肝炎病毒复制的强效抑制作用（半数有效浓度<10 nM），与纯化的NS4B蛋白直接结合（半数抑制浓度<20 nM），以及与NS4B相关的丙型肝炎病毒耐药模式（H94N/R、V105L/M、F98L），这些在已报道的丙型肝炎病毒临床药物中是独特的，表明与其他丙型肝炎病毒复制小分子抑制剂联合使用具有相加或协同作用的潜力。
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本文引用的文献
1
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Nat Biotechnol. 2011 Nov 8;29(11):993-1003. doi: 10.1038/nbt.2020.
2
Drugs in development for chronic hepatitis C: a promising future.开发中的慢性丙型肝炎药物：前景广阔。
Expert Opin Biol Ther. 2011 Dec;11(12):1611-22. doi: 10.1517/14712598.2011.627851. Epub 2011 Oct 13.
3
Directly acting antivirals against hepatitis C virus.直接作用的抗丙型肝炎病毒药物。
J Antimicrob Chemother. 2011 Aug;66(8):1673-86. doi: 10.1093/jac/dkr215. Epub 2011 Jun 7.
4
New opportunities in anti-hepatitis C virus drug discovery: targeting NS4B.抗丙型肝炎病毒药物研发的新机遇：针对 NS4B。
Antiviral Res. 2011 May;90(2):93-101. doi: 10.1016/j.antiviral.2011.01.009. Epub 2011 Feb 2.
5
The Journey to the Discovery of Boceprevir: an NS3-NS4 HCV protease inhibitor for the treatment of chronic hepatitis C.博赛泼维的发现之旅：一种用于治疗慢性丙型肝炎的NS3-NS4丙型肝炎病毒蛋白酶抑制剂
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6
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7
New therapeutic prospects in HCV treatment.
Expert Rev Anti Infect Ther. 2008 Dec;6(6):775-9. doi: 10.1586/14787210.6.6.775.
8
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Expert Rev Anti Infect Ther. 2008 Aug;6(4):463-78. doi: 10.1586/14787210.6.4.463.
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J Virol. 2002 Apr;76(8):4008-21. doi: 10.1128/jvi.76.8.4008-4021.2002.
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