Structure-Guided Design of Novel, Potent, and Selective Macrocyclic Plasma Kallikrein Inhibitors

详细信息    查看全文

• 作者：Zhe LiJames Partridge ; Abel Silva-Garcia ; Peter Rademacher ; Andreas Betz ; Qing Xu ; Hing Sham ; Yunjin Hu ; Yuqing Shan ; Bin Liu ; Ying Zhang ; Haijuan Shi ; Qiong Xu ; Xubo Ma ; Li Zhang
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：February 9, 2017
• 年：2017
• 卷：8
• 期：2
• 页码：185-190
• 全文大小：416K
• ISSN：1948-5875

文摘

A series of macrocyclic analogues were designed and synthesized based on the cocrystal structure of small molecule plasma kallikrein (pKal) inhibitor, 2, with the pKal protease domain. This led to the discovery of a potent macrocyclic pKal inhibitor 29, with an IC₅₀ of 2 nM for one olefinic isomer and 42.3 nM for the other olefinic isomer.