Benzimidazole derivatives bearing substituted biphenyls as hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors: Structure-activity relationship studies and identification of a potent and highly selective inhibitor JTK-109

Hirashima S; Suzuki T; Ishida T; Noji S; Yata S; Ando I; Komatsu M; Ikeda S; Hashimoto H

首页> 外文期刊>Journal of Medicinal Chemistry >Benzimidazole derivatives bearing substituted biphenyls as hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors: Structure-activity relationship studies and identification of a potent and highly selective inhibitor JTK-109

【24h】

Benzimidazole derivatives bearing substituted biphenyls as hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors: Structure-activity relationship studies and identification of a potent and highly selective inhibitor JTK-109

机译：带有取代联苯的苯并咪唑衍生物作为丙型肝炎病毒NS5B RNA依赖性RNA聚合酶抑制剂：结构与活性的关系研究以及强效和高度选择性抑制剂JTK-109的鉴定

获取原文

获取原文并翻译 | 示例

掌桥外文数据库（机构版） >>

开具论文收录证明 >>

文献代查 >>

页面导航

摘要
著录项
相似文献
相关主题

摘要

Following the discovery of a new series of benzimidazole derivatives bearing a diarylmethyl group as inhibitors of hepatitis C virus NS5B RNA-dependent RNA polymerase (HCV NS5B RdRp), 1,2 we extended the structure-activity relationship (SAR) study to analogues bearing a substituted biphenyl group and succeeded in a significant advancement of activity. Starting from compound 1, optimization of the A, B, and C rings afforded potent inhibitors with low nanomolar potency against genotype 1b NS5B. The compounds, which have a substituent with a carbonyl function at the 4-position of the B-ring, efficiently blocked subgenomic viral RNA replication in the replicon cell assay at low submicromolar concentrations. Among the new compounds, compound 10n (JTK-109) exhibited favorable pharmacokinetic profiles, high selectivity for NS5B, and good safety profiles, suggesting the potential for a clinical candidate in the treatment of hepatitis C.

机译：继发现一系列新的带有二芳基甲基的苯并咪唑衍生物作为丙型肝炎病毒NS5B RNA依赖性RNA聚合酶（HCV NS5B RdRp）的抑制剂后，1,2，我们将结构活性关系（SAR）研究扩展到了带有甲氧西林的类似物。取代联苯基团，并成功地大大提高了活性。从化合物1开始，对A，B和C环进行优化可提供对基因型1b NS5B具有低纳摩尔效价的强效抑制剂。这些化合物在B环的4位带有一个具有羰基官能团的取代基，可在复制子细胞测定中以低亚微摩尔浓度有效阻断亚基因组病毒RNA复制。在新化合物中，化合物10n（JTK-109）表现出良好的药代动力学特征，对NS5B的高选择性和良好的安全性特征，表明在治疗丙型肝炎方面具有临床潜力。

著录项

来源
《Journal of Medicinal Chemistry》 |2006年第15期|共16页
作者
Hirashima S; Suzuki T; Ishida T; Noji S; Yata S; Ando I; Komatsu M; Ikeda S; Hashimoto H;
展开▼
作者单位

展开▼
收录信息
原文格式 PDF
正文语种 eng
中图分类药学;
关键词
ALLOSTERIC INHIBITORS; REPLICATION; CULTURE; ACIDS;

机译：异位抑制剂;复制;文化;酸;

相似文献

外文文献
中文文献
专利

1. Benzimidazole derivatives bearing substituted biphenyls as hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors: Structure-activity relationship studies and identification of a potent and highly selective inhibitor JTK-109 [J] . Hirashima S, Suzuki T, Ishida T, Journal of Medicinal Chemistry . 2006,第15期

机译：带有取代联苯的苯并咪唑衍生物作为丙型肝炎病毒NS5B RNA依赖性RNA聚合酶抑制剂：结构与活性的关系研究以及强效和高度选择性抑制剂JTK-109的鉴定
2. Parallel synthesis of pteridine derivatives as potent inhibitors for hepatitis C virus NS5B RNA-dependent RNA polymerase. [J] . Ding Y, Girardet JL, Smith KL, Bioorganic and Medicinal Chemistry Letters . 2005,第3期

机译：并行合成蝶啶衍生物作为丙型肝炎病毒NS5B RNA依赖性RNA聚合酶的有效抑制剂。
3. Discovery of α,γ-Diketo Acids as Potent Selective and Reversible Inhibitors of Hepatitis C Virus NS5b RNA-Dependent RNA Polymerase [J] . Vincenzo Summa, Alessia Petrocchi, Paola Pace, Journal of Medicinal Chemistry . 2004,第1期

机译：发现作为丙型肝炎病毒NS5b RNA依赖性RNA聚合酶的强效选择性和可逆抑制剂的α，γ-二酮酸
4. Inhibitor Candidates's Identification of HCV's RNA polymerase NS5B Using Virtual Screening against iPPI-library [C] . Indah Sulistyawati, Sulistyo Dwi K.P, Mochammad Ichsan International Conference and Workshop on Basic and Applied Sciences . 2016

机译：抑制剂候选候选HCV的RNA聚合酶NS5B使用虚拟筛选对IPPI-LIBRINT的鉴定
5. Part I: Synthesis of 2'-Fluoro-2',3'-Dideoxynucleosides as Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase. Part II: Synthesis of Cyclobutyl Phosphonate and Phosphoramidate Prodrugs for Inhibition of HIV Reverse Transcriptase [D] . Neuman, Annette Welty 2013

机译：第一部分：2'-Fluoro-2'，3'-Dideoxynucleosides的合成作为丙型肝炎病毒RNA依赖性RNA聚合酶的抑制剂。第二部分：抑制HIV逆转录酶的膦酸环丁酯和氨基磷酸酯前药的合成
6. Identification and Analysis of Novel Inhibitors against NS3 Helicase and NS5B RNA-Dependent RNA Polymerase from Hepatitis C Virus 1b (Con1) [O] . Na Yang, Chaomin Sun, Lixin Zhang, -1

机译：鉴定和分析新型抗丙型肝炎病毒1b（Con1）的NS3解旋酶和NS5B RNA依赖性RNA聚合酶抑制剂
7. A Highly Efficient, Asymmetric Synthesis of Benzothiadiazine-Substituted Tetramic Acids: Potent Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase. [O] . Duke M. Fitch, Karen A. Evans, Deping Chai, 2006

机译：苯并噻嗪取代的四酸的高效，不对称合成：丙型肝炎病毒RNA依赖性RNA聚合酶的有效抑制剂。

Benzimidazole derivatives bearing substituted biphenyls as hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors: Structure-activity relationship studies and identification of a potent and highly selective inhibitor JTK-109

摘要

著录项

相似文献

相关主题

期刊订阅