Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms

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• 作者：Ling TongWensheng Yu ; Lei ChenOleg Selyutin ; Michael P. Dwyer ; Anilkumar G. Nair ; Robert Mazzola ; Jae-Hun Kim ; Deyou Sha ; Jingjun Yin ; Rebecca T. Ruck ; Ian W. Davies ; Bin Hu ; Bin Zhong ; Jinglai Hao ; Tao Ji ; Shuai Zan ; Rong Liu ; Sony Agrawal ; Ellen Xia ; Stephanie Curry ; Patricia McMonagle ; Karin Bystol ; Frederick Lahser ; Donna Carr ; Laura Rokosz ; Paul Ingravallo ; Shiying Chen ; Kung-I Feng ; Mark Cartwright ; Ernest Asante-Appiah ; Joseph A. Kozlowski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：January 12, 2017
• 年：2017
• 卷：60
• 期：1
• 页码：290-306
• 全文大小：937K
• ISSN：1520-4804

文摘

We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a “flat” GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole–proline–valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.