麻疹病毒RNA依赖性RNA聚合酶复合物的强效非核苷抑制剂。
Potent non-nucleoside inhibitors of the measles virus RNA-dependent RNA polymerase complex.
作者信息
Sun Aiming, Yoon Jeong-Joong, Yin Yan, Prussia Andrew, Yang Yutao, Min Jaeki, Plemper Richard K, Snyder James P
机构信息
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA.
出版信息
J Med Chem. 2008 Jul 10;51(13):3731-41. doi: 10.1021/jm701239a. Epub 2008 Jun 5.
Abstract
Measles virus (MV) is one of the most infectious pathogens known. In spite of the existence of a vaccine, approximately 350000 deaths/year result from MV or associated complications. Antimeasles compounds could conceivably diminish these statistics and provide a therapy that complements vaccine treatment. We recently described a high-throughput screening hit compound 1 (16677) against MV-infected cells with the capacity to eliminate viral reproduction at 250 nM by inhibiting the action of the virus's RNA-dependent RNA polymerase complex (RdRp). The compound, 1-methyl-3-(trifluoromethyl)- N-[4-sulfonylphenyl]-1 H-pyrazole-5-carboxamide, 1 carries a critical CF 3 moiety on the 1,2-pyrazole ring. Elaborating on the preliminary structure-activity (SAR) study, the present work presents the synthesis and SAR of a much broader range of low nanomolar nonpeptidic MV inhibitors and speculates on the role of the CF 3 functionality.
摘要
麻疹病毒（MV）是已知传染性最强的病原体之一。尽管有疫苗存在，但每年仍有大约350000人死于MV或相关并发症。抗麻疹化合物有望改善这些统计数据，并提供一种补充疫苗治疗的疗法。我们最近描述了一种针对MV感染细胞的高通量筛选命中化合物1（16677），它能够通过抑制病毒的RNA依赖性RNA聚合酶复合物（RdRp）的作用，在250 nM浓度下消除病毒繁殖。该化合物1-甲基-3-（三氟甲基）-N-[4-磺酰基苯基]-1H-吡唑-5-甲酰胺（1）在1,2-吡唑环上带有一个关键的CF3基团。在初步构效关系（SAR）研究的基础上，本工作展示了一系列更广泛的低纳摩尔非肽类MV抑制剂的合成及SAR，并推测了CF3官能团的作用。
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