Tetrahydropyrrolo-diazepenones as inhibitors of ERK2 kinase

被引：26
作者：
Bagdanoff, Jeffrey T. [1 ]
Jain, Rama [2 ]
Han, Wooseok [2 ]
Zhu, Shejin [2 ]
Madiera, Ann-Marie [2 ]
Lee, Patrick S. [2 ]
Ma, Xiaolei [2 ]
Poon, Daniel [2 ]
机构：
[1] Novartis Inst BioMed Res, Global Discovery Chem Oncol & Exploratory Chem, Cambridge, MA 02139 USA
[2] Novartis Inst BioMed Res, Global Discovery Chem Oncol & Exploratory Chem, Emeryville, CA 94608 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 18期
关键词：
ERK2; kinase; Structure based drug design; Extraction ratio; ATP binding cleft; Lower-hinge lysine; BRAF-MUTANT; DISCOVERY;
D O I：
10.1016/j.bmcl.2015.07.091
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A series of structure based drug design hypotheses and focused screening efforts led to the identification of tetrahydropyrrolo-diazepenones with striking potency against ERK2 kinase. The role of fluorination in mitigating microsomal clearance was systematically explored. Ultimately, it was found that fluorination of a cyclopentanol substructure provided significant improvement in both potency and human metabolic stability. (C) 2015 Elsevier Ltd. All rights reserved.
引用
收藏
页码：3788 / 3792
页数：5
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