Discovery of 3-alkyl-5-aryl-1-pyrimidyl-1H-pyrazole derivatives as a novel selective inhibitor scaffold of JNK3
Discovery of 3-alkyl-5-aryl-1-pyrimidyl-1H-pyrazole derivatives as a novel selective inhibitor scaffold of JNK3
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DOI：
10.1080/14756366.2019.1705294
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发表时间：
2020-01-01
影响因子：
5.6
通讯作者：
Hah, Jung-Mi
中科院分区：
文献类型：
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作者：
Oh, Youri;Jang, Miyoung;Hah, Jung-Mi
设计并合成了3-烷基-5-芳基-1-嘧啶基-1H-吡唑衍生物作为JNK 3的选择性抑制剂，JNK 3是治疗神经退行性疾病的靶点。根据先前的研究，我们设计了JNK 3抑制剂以降低分子量，并成功鉴定了对JNK 3表现出等效活性的先导化合物。激酶谱分析结果还显示，在38种激酶中，JNK 3具有高选择性。在这些衍生物中，8a，（R）-2-（1-（2-（（1-（环丙烷羰基）吡咯烷-3-基）氨基）嘧啶-4-基）-5-（3，4-二氯苯基）-1H-吡唑-3-基）乙腈的IC 50值显示出227 nM，显示出对JNK 3的最高抑制活性。
3-alkyl-5-aryl-1-pyrimidyl-1H-pyrazole derivatives were designed and synthesised as selective inhibitors of JNK3, a target for the treatment of neurodegenerative diseases. Following previous studies, we have designed JNK3 inhibitors to reduce the molecular weight and successfully identified a lead compound that exhibits equipotent activity towards JNK3. Kinase profiling results also showed high selectivity for JNK3 among 38 kinases. Among the derivatives, the IC50 value of 8a, (R)-2-(1-(2-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl)-5-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)acetonitrile exhibited 227 nM, showing the highest inhibitory activity against JNK3.