丙型肝炎病毒NS5B聚合酶的全基因型引物结合抑制剂的发现。
The discovery of a pan-genotypic, primer grip inhibitor of HCV NS5B polymerase.
作者信息
Eastman Kyle J, Parcella Kyle, Yeung Kap-Sun, Grant-Young Katharine A, Zhu Juliang, Wang Tao, Zhang Zhongxing, Yin Zhiwei, Beno Brett R, Sheriff Steven, Kish Kevin, Tredup Jeffrey, Jardel Adam G, Halan Vivek, Ghosh Kaushik, Parker Dawn, Mosure Kathy, Fang Hua, Wang Ying-Kai, Lemm Julie, Zhuo Xiaoliang, Hanumegowda Umesh, Rigat Karen, Donoso Maria, Tuttle Maria, Zvyaga Tatyana, Haarhoff Zuzana, Meanwell Nicholas A, Soars Matthew G, Roberts Susan B, Kadow John F
机构信息
Bristol-Myers Squibb Pharmaceutical Research and Development , Department of Discovery Chemistry and Molecular Technologies , 5 Research Parkway , Wallingford , Connecticut , USA . Email:
出版信息
Medchemcomm. 2017 Feb 8;8(4):796-806. doi: 10.1039/c6md00636a. eCollection 2017 Apr 1.
Abstract
The development of a series of novel 7-azabenzofurans exhibiting pan-genotype inhibition of HCV NS5B polymerase binding to the primer grip site is presented. Many challenges, including poor oral bioavailability, high clearance, bioactivation, high human serum shift, and metabolic stability were encountered and overcome through SAR studies. This work culminated in the selection of BMS-986139 () as a preclinical candidate.
摘要
本文介绍了一系列新型7-氮杂苯并呋喃的研发情况，这些化合物对丙型肝炎病毒（HCV）NS5B聚合酶与引物结合位点具有泛基因型抑制作用。通过构效关系（SAR）研究，我们遇到并克服了许多挑战，包括口服生物利用度差、高清除率、生物活化、高人体血清迁移率和代谢稳定性等问题。这项工作最终筛选出BMS-986139（）作为临床前候选药物。
相似文献
1
The discovery of a pan-genotypic, primer grip inhibitor of HCV NS5B polymerase.丙型肝炎病毒NS5B聚合酶的全基因型引物结合抑制剂的发现。
Medchemcomm. 2017 Feb 8;8(4):796-806. doi: 10.1039/c6md00636a. eCollection 2017 Apr 1.
2
Improving Metabolic Stability with Deuterium: The Discovery of BMT-052, a Pan-genotypic HCV NS5B Polymerase Inhibitor.利用氘提高代谢稳定性：泛基因型丙型肝炎病毒NS5B聚合酶抑制剂BMT-052的发现
ACS Med Chem Lett. 2017 Jun 29;8(7):771-774. doi: 10.1021/acsmedchemlett.7b00211. eCollection 2017 Jul 13.
3
Combination therapies with NS5A, NS3 and NS5B inhibitors on different genotypes of hepatitis C virus in human hepatocyte chimeric mice.在人源化肝细胞嵌合小鼠中，针对丙型肝炎病毒不同基因型的 NS5A、NS3 和 NS5B 抑制剂联合治疗。
Gut. 2013 Jul;62(7):1055-61. doi: 10.1136/gutjnl-2012-302600. Epub 2013 Jan 15.
4
Preclinical characterization of BMS-791325, an allosteric inhibitor of hepatitis C Virus NS5B polymerase.丙肝病毒NS5B聚合酶变构抑制剂BMS-791325的临床前特性研究
Antimicrob Agents Chemother. 2014 Jun;58(6):3485-95. doi: 10.1128/AAC.02495-13. Epub 2014 Apr 14.
5
Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase.发现三环 5,6-二氢-1H-吡啶-2-酮类化合物作为新型、有效和口服生物利用度的 HCV NS5B 聚合酶抑制剂。
Bioorg Med Chem Lett. 2009 Nov 15;19(22):6404-12. doi: 10.1016/j.bmcl.2009.09.045. Epub 2009 Sep 17.
6
Mechanism of inhibition for BMS-791325, a novel non-nucleoside inhibitor of hepatitis C virus NS5B polymerase.新型丙型肝炎病毒NS5B聚合酶非核苷抑制剂BMS-791325的抑制机制
J Biol Chem. 2014 Nov 28;289(48):33456-68. doi: 10.1074/jbc.M114.613653. Epub 2014 Oct 9.
7
Chemical genetics-based discovery of indole derivatives as HCV NS5B polymerase inhibitors.基于化学遗传学发现吲哚衍生物作为丙型肝炎病毒NS5B聚合酶抑制剂
Eur J Med Chem. 2014 Mar 21;75:413-25. doi: 10.1016/j.ejmech.2014.01.062. Epub 2014 Jan 31.
8
Discovery and initial optimization of alkoxyanthranilic acid derivatives as inhibitors of HCV NS5B polymerase.发现并初步优化烷氧基邻氨基苯甲酸衍生物作为丙型肝炎病毒NS5B聚合酶抑制剂。
Bioorg Med Chem Lett. 2017 Jan 15;27(2):295-298. doi: 10.1016/j.bmcl.2016.11.054. Epub 2016 Nov 22.
9
Specific inhibitors of HCV polymerase identified using an NS5B with lower affinity for template/primer substrate.使用对模板/引物底物亲和力较低的NS5B鉴定出的丙型肝炎病毒聚合酶特异性抑制剂。
Nucleic Acids Res. 2004 Jan 22;32(2):422-31. doi: 10.1093/nar/gkh160. Print 2004.
10
Discovery of novel Hepatitis C virus inhibitor targeting multiple allosteric sites of NS5B polymerase.发现靶向 NS5B 聚合酶多个变构位点的新型丙型肝炎病毒抑制剂。
Infect Genet Evol. 2020 Oct;84:104371. doi: 10.1016/j.meegid.2020.104371. Epub 2020 May 31.
引用本文的文献
1
Virtual screening, optimization design, and synthesis analysis of novel benzofuran derivatives as pan-genotypic HCV NS5B polymerase inhibitors using molecular modeling.利用分子建模对新型苯并呋喃衍生物作为泛基因型丙型肝炎病毒NS5B聚合酶抑制剂进行虚拟筛选、优化设计及合成分析。
BMC Chem. 2025 Jul 4;19(1):199. doi: 10.1186/s13065-025-01575-2.
2
Discovery of a non-nucleoside inhibitor that binds to a novel site in the palm domain of the respiratory syncytial virus RNA-dependent RNA polymerase.发现一种非核苷抑制剂，其与呼吸道合胞病毒RNA依赖性RNA聚合酶掌状结构域中的一个新位点结合。
J Virol. 2025 Jul 22;99(7):e0017825. doi: 10.1128/jvi.00178-25. Epub 2025 Jun 2.
3
Distinct Characteristic Binding Modes of Benzofuran Core Inhibitors to Diverse Genotypes of Hepatitis C Virus NS5B Polymerase: A Molecular Simulation Study.苯并呋喃核心抑制剂与丙型肝炎病毒 NS5B 聚合酶不同基因型的独特结合模式：分子模拟研究。
Int J Mol Sci. 2024 Jul 23;25(15):8028. doi: 10.3390/ijms25158028.
4
-Heterocycles as Promising Antiviral Agents: A Comprehensive Overview.杂环化合物作为有前途的抗病毒药物：全面概述。
Molecules. 2024 May 10;29(10):2232. doi: 10.3390/molecules29102232.
5
Concise, gram-scale synthesis of furo[2,3-]pyridines with functional handles for chemoselective cross-coupling.简洁的克级规模合成带有用于化学选择性交叉偶联的功能手柄的呋喃并[2,3-]吡啶。
Tetrahedron Lett. 2020 Sep 17;61(38). doi: 10.1016/j.tetlet.2020.152353. Epub 2020 Aug 16.
6
Structure-Property Basis for Solving Transporter-Mediated Efflux and Pan-Genotypic Inhibition in HCV NS5B Inhibitors.解决丙型肝炎病毒NS5B抑制剂中转运蛋白介导的外排和泛基因型抑制问题的结构-性质基础
ACS Med Chem Lett. 2018 Nov 5;9(12):1217-1222. doi: 10.1021/acsmedchemlett.8b00379. eCollection 2018 Dec 13.
7
NMR reveals the intrinsically disordered domain 2 of NS5A protein as an allosteric regulator of the hepatitis C virus RNA polymerase NS5B.核磁共振揭示了NS5A蛋白的内在无序结构域2作为丙型肝炎病毒RNA聚合酶NS5B的变构调节剂。
J Biol Chem. 2017 Nov 3;292(44):18024-18043. doi: 10.1074/jbc.M117.813766. Epub 2017 Sep 14.
8
Improving Metabolic Stability with Deuterium: The Discovery of BMT-052, a Pan-genotypic HCV NS5B Polymerase Inhibitor.利用氘提高代谢稳定性：泛基因型丙型肝炎病毒NS5B聚合酶抑制剂BMT-052的发现
ACS Med Chem Lett. 2017 Jun 29;8(7):771-774. doi: 10.1021/acsmedchemlett.7b00211. eCollection 2017 Jul 13.
本文引用的文献
1
Discovery and initial optimization of alkoxyanthranilic acid derivatives as inhibitors of HCV NS5B polymerase.发现并初步优化烷氧基邻氨基苯甲酸衍生物作为丙型肝炎病毒NS5B聚合酶抑制剂。
Bioorg Med Chem Lett. 2017 Jan 15;27(2):295-298. doi: 10.1016/j.bmcl.2016.11.054. Epub 2016 Nov 22.
2
Phosphocholine conjugation: an unexpected in vivo conjugation pathway associated with hepatitis c ns5b inhibitors featuring a bicyclo[1.1.1]pentane.
Drug Metab Dispos. 2016 Aug;44(8):1332-1340. doi: 10.1124/dmd.115.069062. Epub 2016 Mar 9.
3
Hepatitis C virus genotype 7, a new genotype originating from central Africa.丙型肝炎病毒基因7型，一种源自中非的新型基因型。
J Clin Microbiol. 2015 Mar;53(3):967-72. doi: 10.1128/JCM.02831-14. Epub 2014 Dec 17.
4
The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection.asunaprevir（BMS-650032）的发现，一种口服有效的 NS3 蛋白酶抑制剂，用于治疗丙型肝炎病毒感染。
J Med Chem. 2014 Mar 13;57(5):1730-52. doi: 10.1021/jm500297k. Epub 2014 Mar 5.
5
Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.丙型肝炎病毒 NS5A 复制复合物抑制剂：达卡他韦的发现。
J Med Chem. 2014 Mar 13;57(5):2013-32. doi: 10.1021/jm401836p. Epub 2014 Feb 12.
6
Discovery and preclinical characterization of the cyclopropylindolobenzazepine BMS-791325, a potent allosteric inhibitor of the hepatitis C virus NS5B polymerase.发现并临床前表征环丙基吲哚苯并氮杂䓬 BMS-791325，一种有效的丙型肝炎病毒 NS5B 聚合酶变构抑制剂。
J Med Chem. 2014 Mar 13;57(5):1855-79. doi: 10.1021/jm4016894. Epub 2014 Jan 7.
7
Quantifying the diversification of hepatitis C virus (HCV) during primary infection: estimates of the in vivo mutation rate.定量原发性丙型肝炎病毒（HCV）感染期间的多样性：体内突变率的估计。
PLoS Pathog. 2012;8(8):e1002881. doi: 10.1371/journal.ppat.1002881. Epub 2012 Aug 23.
8
Scalable synthesis of 1-bicyclo[1.1.1]pentylamine via a hydrohydrazination reaction.通过氢肼化反应可规模化合成 1-双环[1.1.1]戊基胺。
Org Lett. 2011 Sep 2;13(17):4746-8. doi: 10.1021/ol201883z. Epub 2011 Aug 11.
9
Severe hepatocellular injury with apoptosis induced by a hepatitis C polymerase inhibitor.丙型肝炎病毒聚合酶抑制剂诱导的伴有凋亡的严重肝细胞损伤
J Clin Gastroenterol. 2009 Apr;43(4):374-81. doi: 10.1097/MCG.0b013e318178d91f.
10
HCV796: A selective nonstructural protein 5B polymerase inhibitor with potent anti-hepatitis C virus activity in vitro, in mice with chimeric human livers, and in humans infected with hepatitis C virus.HCV796：一种选择性非结构蛋白5B聚合酶抑制剂，在体外、具有嵌合人肝脏的小鼠以及丙型肝炎病毒感染的人类中具有强大的抗丙型肝炎病毒活性。
Hepatology. 2009 Mar;49(3):745-52. doi: 10.1002/hep.22717.
Zotero 插件