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

被引：20

作者：

Li, Zhe ^{[1
]}

Partridge, James ^{[1
]}

Silva-Garcia, Abel ^{[1
]}

Rademacher, Peter ^{[1
]}

Betz, Andreas ^{[1
]}

Xu, Qing ^{[1
]}

Sham, Hing ^{[1
]}

Hu, Yunjin ^{[2
]}

Shan, Yuqing ^{[2
]}

Liu, Bin ^{[2
]}

Zhang, Ying ^{[2
]}

Shi, Haijuan ^{[2
]}

Xu, Qiong ^{[2
]}

Ma, Xubo ^{[2
]}

Zhang, Li ^{[2
]}

机构：

[1] Global Blood Therapeut, San Francisco, CA 94080 USA

[2] Pharmaron Xian Co, Xian 710018, Shaanxi, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 02期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

Hereditary angioedema; plasma kallikrein; protease inhibitor; structure-based design; macrocycle; CONFORMATIONAL RESTRICTION; OLEFIN METATHESIS; HETEROCYCLES; TRIAL;

D O I：

10.1021/acsmedchemlett.6b00384

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：185 / 190

页数：6

共 17 条

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