Discovery of MK-6169, a Potent Pan-Genotype Hepatitis C Virus NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Substitutions,Journal of Medicinal Chemistry

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Discovery of MK-6169, a Potent Pan-Genotype Hepatitis C Virus NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Substitutions
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-04-21 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01927
Wensheng Yu , Ling Tong , Oleg Selyutin , Lei Chen , Bin Hu ₁ , Bin Zhong ₁ , Jinglai Hao ₁ , Tao Ji ₁ , Shuai Zan ₁ , Jingjun Yin , Rebecca T Ruck , Stephanie Curry , Patricia McMonagle , Sony Agrawal , Laura Rokosz , Donna Carr , Paul Ingravallo , Karin Bystol , Frederick Lahser , Rong Liu , Shiying Chen , Kung-I Feng , Mark Cartwright , Ernest Asante-Appiah , Joseph A Kozlowski

Affiliation

We describe the discovery of MK-6169, a potent and pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir led to the discovery of a series of compounds with substantially improved potency against common resistance-associated substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (21) was discovered as a preclinical candidate for further development.

中文翻译：

发现 MK-6169，一种有效的泛基因型丙型肝炎病毒 NS5A 抑制剂，对常见的耐药相关替代物具有优化的活性

我们描述了 MK-6169 的发现，这是一种有效的泛基因型丙型肝炎病毒 NS5A 抑制剂，具有针对常见耐药相关替代物的优化活性。围绕 elbasvir 缬氨酸和氨基碳区域变化组合的 SAR 研究导致发现了一系列化合物，这些化合物对主要基因型中常见的耐药性相关取代具有显着提高的效力，并且在大鼠和大鼠中均具有良好的药代动力学。狗。通过进一步优化这项工作的关键线索，发现 MK-6169 ( 21 ) 作为进一步开发的临床前候选药物。

更新日期：2018-04-21

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