Design and Synthesis of P2–P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors

详细信息    查看全文

• 作者：Francisco Velázquez ; Mariappan Chelliah ; Martin Clasby ; Zhuyan Guo ; John Howe ; Randy Miller ; Santhosh Neelamkavil ; Unmesh Shah ; Aileen Soriano ; Yan Xia ; Srikanth Venkatraman ; Samuel Chackalamannil ; Ian W. Davies
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：7
• 期：12
• 页码：1173-1178
• 全文大小：311K
• ISSN：1948-5875

文摘

A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline–P2 surrogate onto the P2–P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC₅₀ values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia–Kocienski olefination and macrolactamization to assemble the P2–P4 macrocyclic core containing the novel spirocyclic proline–P2 moiety is presented as well.