Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome

被引：35

作者：

Lynch, Stephen M. ^{[1
]}

DeVicente, Javier ^{[1
]}

Hermann, Johannes C. ^{[1
]}

Jaime-Figueroa, Saul ^{[1
]}

Jin, Sue ^{[2
]}

Kuglstatter, Andreas ^{[3
]}

Li, Hongju ^{[1
]}

Lovey, Allen ^{[1
]}

Menke, John ^{[2
]}

Niu, Linghao ^{[2
]}

Patel, Vaishali ^{[2
]}

Roy, Douglas ^{[1
]}

Soth, Michael ^{[1
]}

Steiner, Sandra ^{[1
]}

Tivitmahaisoon, Parcharee ^{[1
]}

Minh Diem Vu ^{[2
]}

Yee, Calvin ^{[1
]}

机构：

[1] Hoffmann La Roche Inc, Discovery Chem, pRED, Nutley, NJ 07110 USA

[2] Hoffmann La Roche Inc, Inflammat Biol, pRED, Nutley, NJ 07110 USA

[3] Hoffmann La Roche Inc, Discovery Technol, pRED, Nutley, NJ 07110 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 09期

关键词：

Kinase inhibitors; Janus kinase; JAK; Structure based design; Kinase selectivity; Conformational bias; RHEUMATOID-ARTHRITIS; JANUS KINASES; TRANSPLANT REJECTION; DISCOVERY; CP-690,550; PSORIASIS; EFFICACY;

D O I：

10.1016/j.bmcl.2013.02.012

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family. (C) 2013 Published by Elsevier Ltd.

引用

页码：2793 / 2800

页数：8

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