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Highlights of the Structure–Activity Relationships of Benzimidazole Linked Pyrrolidines Leading to the Discovery of the Hepatitis C Virus NS5A Inhibitor Pibrentasvir (ABT-530)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-04-13 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00082 Rolf Wagner 1 , John T Randolph 1 , Sachin V Patel 1 , Lissa Nelson 1 , Mark A Matulenko 1 , Ryan Keddy 1 , John K Pratt 1 , Dachun Liu 1 , A Chris Krueger 1 , Pamela L Donner 1 , Douglas K Hutchinson 1 , Charles Flentge 1 , David Betebenner 1 , Todd Rockway 1 , Clarence J Maring 1 , Teresa I Ng 1 , Preethi Krishnan 1 , Tami Pilot-Matias 1 , Christine Collins 1 , Neeta Panchal 1 , Thomas Reisch 1 , Tatyana Dekhtyar 1 , Rubina Mondal 1 , DeAnne F Stolarik 1 , Yi Gao 1 , Wenqing Gao 1 , David A Beno 1 , Warren M Kati 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-04-13 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00082 Rolf Wagner 1 , John T Randolph 1 , Sachin V Patel 1 , Lissa Nelson 1 , Mark A Matulenko 1 , Ryan Keddy 1 , John K Pratt 1 , Dachun Liu 1 , A Chris Krueger 1 , Pamela L Donner 1 , Douglas K Hutchinson 1 , Charles Flentge 1 , David Betebenner 1 , Todd Rockway 1 , Clarence J Maring 1 , Teresa I Ng 1 , Preethi Krishnan 1 , Tami Pilot-Matias 1 , Christine Collins 1 , Neeta Panchal 1 , Thomas Reisch 1 , Tatyana Dekhtyar 1 , Rubina Mondal 1 , DeAnne F Stolarik 1 , Yi Gao 1 , Wenqing Gao 1 , David A Beno 1 , Warren M Kati 1
Affiliation
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Curative interferon and ribavirin sparing treatments for hepatitis C virus (HCV)-infected patients require a combination of mechanistically orthogonal direct acting antivirals. A shared component of these treatments is usually an HCV NS5A inhibitor. First generation FDA approved treatments, including the component NS5A inhibitors, do not exhibit equivalent efficacy against HCV virus genotypes 1–6. In particular, these first generation NS5A inhibitors tend to select for viral drug resistance. Ombitasvir is a first generation HCV NS5A inhibitor included as a key component of Viekira Pak for the treatment of patients with HCV genotype 1 infection. Since the launch of next generation HCV treatments, functional cure for genotype 1–6 HCV infections has been achieved, as well as shortened treatment duration across a wider spectrum of genotypes. In this paper, we show how we have modified the anchor, linker, and end-cap architecture of our NS5A inhibitor design template to discover a next generation NS5A inhibitor pibrentasvir (ABT-530), which exhibits potent inhibition of the replication of wild-type genotype 1–6 HCV replicons, as well as improved activity against replicon variants demonstrating resistance against first generation NS5A inhibitors.
中文翻译：
苯并咪唑连接的吡咯烷的结构与活性关系的重点，导致发现丙型肝炎病毒NS5A抑制剂哌布那斯韦（ABT-530）
丙型肝炎病毒（HCV）感染患者的治疗性干扰素和利巴韦林保留疗法需要机械正交的直接作用抗病毒药的组合。这些治疗的共同成分通常是HCV NS5A抑制剂。包括成分NS5A抑制剂在内的第一代FDA批准的治疗方法，对HCV病毒基因型1-6的疗效均不相同。特别地，这些第一代NS5A抑制剂倾向于选择病毒药物抗性。Ombitasvir是第一代HCV NS5A抑制剂，被列为Viekira Pak的关键成分，用于治疗HCV基因型1感染的患者。自从推出下一代HCV治疗以来，已经实现了针对1-6型HCV基因型感染的功能性治愈，并且缩短了更广泛基因型范围内的治疗时间。
更新日期：2018-04-13
中文翻译：
苯并咪唑连接的吡咯烷的结构与活性关系的重点，导致发现丙型肝炎病毒NS5A抑制剂哌布那斯韦（ABT-530）
丙型肝炎病毒（HCV）感染患者的治疗性干扰素和利巴韦林保留疗法需要机械正交的直接作用抗病毒药的组合。这些治疗的共同成分通常是HCV NS5A抑制剂。包括成分NS5A抑制剂在内的第一代FDA批准的治疗方法，对HCV病毒基因型1-6的疗效均不相同。特别地，这些第一代NS5A抑制剂倾向于选择病毒药物抗性。Ombitasvir是第一代HCV NS5A抑制剂，被列为Viekira Pak的关键成分，用于治疗HCV基因型1感染的患者。自从推出下一代HCV治疗以来，已经实现了针对1-6型HCV基因型感染的功能性治愈，并且缩短了更广泛基因型范围内的治疗时间。
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