3,4-Diaryl-isoxazoles and -imidazoles as Potent Dual Inhibitors of p38α Mitogen Activated Protein Kinase and Casein Kinase 1δ
3,4-Diaryl-isoxazoles and -imidazoles as Potent Dual Inhibitors of p38α Mitogen Activated Protein Kinase and Casein Kinase 1δ
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DOI：
10.1021/jm9005127
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发表时间：
2009-12-10
影响因子：
7.3
通讯作者：
Laufer, Stefan
中科院分区：
文献类型：
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作者：
Peifer, Christian;Abadleh, Mohammed;Laufer, Stefan
在这项研究中，我们报道了异恶唑1作为p38 α (IC50=0.45 μ M)和CK1 δ (IC50=0.23 μ M)的有效双重抑制剂的发现。由于迄今为止只有少数有效的CK1小分子抑制剂被描述，我们的目标是开发这类结构的特异性药物。通过比较p38 α和CK1 δ的分子模型研究，提出了一种优化策略，可设计、合成、生物学表征和合成高效化合物，包括9 （IC50 p38 α =0.006 μ M, IC50 CK1 δ =1.6 μ M）、13（IC50 p38 α =2.52 μ M， IC(50)CK1 δ =0.033 μ M）、17（IC50 p38 α =0.019 μ M, IC50 CK1 δ =0.004 μ M, IC50 CK1 ε =0.073 μ M）和18 (CKP138) （IC50 p38 α =0.041 μ M, IC50 CK1 δ =0.005 μ M, IC50 CK1 δ = 0.05 μ M）。IC50 CK1 epsilon=0.447 μ M)具有分化特异性。选定的化合物在76种激酶上进行了分析，对其细胞功效的评估表明，18（CKP138）是一种高效的、双特异性的CK1 δ和p38 α抑制剂。
In this study, we report on the discovery of isoxazole 1 as a potent dual inhibitor of p38 alpha (IC50=0.45 mu M) and CK1 delta (IC50=0.23 mu M). Because only it few effective small molecule inhibitors of CK1 have been described so far, we aimed to develop this structural class toward specific agents. Molecular modeling studies comparing p38 alpha/CK1 delta suggested an optimization strategy leading to design, synthesis, biological characterization, and SAR of highly potent compounds including 9 (IC50 p38 alpha=0.006 mu M; IC50 CK1 delta=1.6 mu M), 13(IC50 p38 alpha=2.52 mu M; IC(50)CK1 delta=0.033 mu M), 17(IC50 p38 alpha=0.019 mu M; IC50 CK1 delta=0.004 mu M; IC50 CK1 epsilon=0.073 mu M), and 18 (CKP138) (IC50 p38 alpha=0.041 mu M; IC50 CK1 delta=0.005 mu M; IC50 CK1 epsilon=0.447 mu M) possessing differentiated specificity. Selected compounds were profiled over 76 kinases and evaluation of their cellular efficacy showed 18(CKP138) to be a highly potent and dual-specific inhibitor of CK1 delta and p38 alpha.