四取代吡啶基咪唑衍生物作为 p38α 丝裂原活化蛋白激酶和 c-Jun N-末端激酶 3 的双重抑制剂用于治疗神经退行性疾病的潜在用途。
Tetra-substituted pyridinylimidazoles as dual inhibitors of p38α mitogen-activated protein kinase and c-Jun N-terminal kinase 3 for potential treatment of neurodegenerative diseases.
机构信息
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
出版信息
J Med Chem. 2015 Jan 8;58(1):443-56. doi: 10.1021/jm501557a. Epub 2014 Dec 5.
Tetra-substituted imidazoles were designed as dual inhibitors of c-Jun N-terminal kinase (JNK) 3 and p38α mitogen-activated protein (MAP) kinase. A library of 45 derivatives was prepared and evaluated in a kinase activity assay for their ability to inhibit both kinases, JNK3 and p38α MAP kinase. Dual inhibitors with IC50 values down to the low double-digit nanomolar range at both enzymes were identified. The best balanced dual JNK3/p38α MAP kinase inhibitors are 6m (IC50: JNK3, 18 nM; p38α, 30 nM) and 14d (IC50: JNK3, 26 nM; p38α, 34 nM) featuring both excellent solubility and metabolic stability. They may serve as useful tool compounds for preclinical proof-of-principle studies in order to validate the synergistic role of both kinases in the progression of Huntington's disease.
四取代的咪唑类化合物被设计为 c-Jun N 末端激酶（JNK）3 和 p38α 丝裂原活化蛋白（MAP）激酶的双重抑制剂。制备了 45 个衍生物库，并在激酶活性测定中评估了它们抑制两种激酶 JNK3 和 p38α MAP 激酶的能力。鉴定出具有双 IC50 值的双重抑制剂，在两种酶中的值低至低双位数纳摩尔范围。最佳平衡的双重 JNK3/p38α MAP 激酶抑制剂为 6m（IC50：JNK3，18 nM；p38α，30 nM）和 14d（IC50：JNK3，26 nM；p38α，34 nM），兼具出色的溶解性和代谢稳定性。它们可以作为临床前验证两种激酶在亨廷顿病进展中的协同作用的原则性研究的有用工具化合物。
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