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

共 38 条

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Matthews, DA
Dragovich, PS
Webber, SE
Fuhrman, SA
Patick, AK
Zalman, LS
Hendrickson, TF
Love, RA
Prins, TJ
Marakovits, JT
Zhou, R
Tikhe, J
Ford, CE
Meador, JW
Ferre, RA
Brown, EL
Binford, SL
Brothers, MA
DeLisle, DM
Worland, ST
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (20) : 11000 - 11007
[32] The structure-based design of peptidomimetic inhibitors against SARS-CoV-2 3C like protease as Potent anti-viral drug candidate
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Xing, Shuai
Zhang, Yanan
Zhang, Chen
He, Shuai
Sun, Hao
Xiao, Shuqi
Xiong, Jin
Zhang, Yecheng
Chen, Xinwen
Wang, Yaxin
Guo, Yu
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Shang, Luqing
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[37] Structure-Based Optimization of Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Improved Potency against Resistance-Associated Variants
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Fang, Zengjun
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Lu, Xueyi
Zhang, Heng
Xu, Haoran
Huo, Zhipeng
Zhou, Zhongxia
Yu, Zhao
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[38] Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants
Das, K
Clark, AD
Lewi, PJ
Heeres, J
de Jonge, MR
Koymans, LMH
Vinkers, HM
Daeyaert, F
Ludovici, DW
Kukla, MJ
De Corte, B
Kavash, RW
Ho, CY
Ye, H
Lichtenstein, MA
Andries, K
Pauwels, R
de Béthune, MP
Boyer, PL
Clark, P
Hughes, SH
Janssen, PAJ
Arnold, E
JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (10) : 2550 - 2560

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