Synthesis and evaluation of 2-{[2-(4-hydroxyphenyl)-ethyl] amino} pyrimidine-5-carboxamide derivatives as novel STAT6 inhibitors

被引：51
作者：
Nagashima, Shinya
Yokota, Masaki
Nakai, Ei-ichi
Kuromitsu, Sadao
Ohga, Keiko
Takeuchi, Makoto
Tsukamoto, Shin-ichi
Ohta, Mitsuaki
机构：
[1] Astellas Pharma Inc, Inst Drug Discovery Res, Yodogawa Ku, Osaka 5328514, Japan
[2] Inst Drug Discovery Res, Tsukuba, Ibaraki 3058585, Japan
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2007年 / 15卷 / 02期
关键词：
signal transducers and activators of transcription 6; allergic disease; interleukin-4; Th2; differentiation;
D O I：
10.1016/j.bmc.2006.10.015
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
The STAT6 (signal transducers and activators of transcription 6) protein is activated by interleukin (IL)-4 and IL-13, and plays an important role in T-helper cell 2 (Th2) differentiation. STAT6 might therefore be an excellent therapeutic target for various allergic conditions, including asthma and atopic diseases. We synthesized a series of 2-{[2-(4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamide derivatives and evaluated their STAT6 inhibitory activities. Among these compounds, 4-(benzylamino)-2-{[2-(3-chloro-4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamide (2t, AS1517499) showed potent STAT6 inhibition with an IC50 value of 21 nM, and also inhibited IL-4-induced Th2 differentiation of mouse spleen T cells with an IC50 value of 2.3 nM and without influencing T-helper cell 1 (Th1) differentiation induced by IL-12. (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码：1044 / 1055
页数：12
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