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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Discovery of piperidinyl aminopyrimidine derivatives as IKK-2 inhibitors.
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Discovery of piperidinyl aminopyrimidine derivatives as IKK-2 inhibitors.

机译：发现哌啶基氨基嘧啶衍生物作为IKK-2抑制剂。

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摘要

A serine-threonine kinase IKK-2 plays an important role in activation of NF-kappaB through phosphorylation of the inhibitor of NF-kappaB (IkappaB). As NF-kappaB is a major transcription factor that regulates genes responsible for cell proliferation and inflammation, development of selective IKK-2 inhibitors has been an important area of anti-inflammatory and anti-cancer research. In this study, to obtain active and selective IKK-2 inhibitors, various substituents were introduced to a piperidinyl aminopyrimidine core structure. The structure-activity relationship study indicated that hydrogen, methanesulfonyl, and aminosulfonyl groups substituted at the piperidinylamino functionality provide high inhibitory activity against IKK-2. Also, morpholinosulfonyl and piperazinosulfonyl group substituted at the aromatic ring attached to the aminopyrimidine core significantly increased the inhibitory activity of the resulting derivatives. In particular, compound 17 with the aromatic piperazinosulfonyl substituent showed the most potent (IC(50)=1.30 muM) and selective (over other kinases such as p38alpha, p38beta, JNK1, JNK2, JNK3, and IKK-1) inhibitory activity against IKK-2.
机译：丝氨酸-苏氨酸激酶IKK-2通过NF-κB抑制剂（IkappaB）的磷酸化在NF-κB活化中起重要作用。由于NF-κB是调节负责细胞增殖和炎症的基因的主要转录因子，因此选择性IKK-2抑制剂的开发一直是抗炎和抗癌研究的重要领域。在这项研究中，为了获得活性和选择性的IKK-2抑制剂，各种取代基被引入到哌啶基氨基嘧啶核心结构中。结构-活性关系研究表明，在哌啶基氨基官能团上取代的氢，甲磺酰基和氨基磺酰基提供了对IKK-2的高抑制活性。同样，在与氨基嘧啶核连接的芳环上取代的吗啉代磺酰基和哌嗪子磺酰基显着提高了所得衍生物的抑制活性。特别是，具有芳香族哌嗪酮磺酰基取代基的化合物17对IKK表现出最强的抑制活性（IC（50）= 1.30μM）和选择性（相对于其他激酶，例如p38alpha，p38beta，JNK1，JNK2，JNK3和IKK-1） -2。

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