As members of the MAPK family, c-Jun-N-terminal kinases (JNKs) regulate the biological processes of apoptosis. In particular, the isoform JNK3 is expressed explicitly in the brain at high levels and is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In this study, we prepared a series of five 6-dihydroxy-1H-benzo[d]imidazoles as JNK3 inhibitors and found them have potential as neuroprotective agents. Following a previous lead scaffold, benzimidazole moiety was modified with various aryl groups and hydroxylation, and the resulting compounds exhibited JNK3 inhibitory activity with improved potency and selectivity. Out of 37 analogues synthesized, (S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][¹,⁴]dioxin -6-yl)-5,6-dihydroxy-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino) piperidin-1-yl)methanone (35b) demonstrated the highest JNK3 inhibition (IC₅₀ = 9.7 nM), as well as neuroprotective effects against Aβ-induced neuronal cell death. As a protein kinase inhibitor, it also showed excellent selectivity over other protein kinases including isoforms JNK1 (>1000 fold) and JNK2 (–10 fold).

中文翻译：

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发现一种对原代大鼠神经元淀粉样蛋白 β 诱导的神经毒性具有神经保护作用的强效选择性 JNK3 抑制剂

作为 MAPK 家族的成员，c-Jun-N 末端激酶 (JNK) 调节细胞凋亡的生物学过程。特别是，同工型 JNK3 在大脑中以高水平明确表达，并参与神经退行性疾病的发病机制，如阿尔茨海默病 (AD) 和帕金森病 (PD)。在这项研究中，我们制备了一系列 5 种 6-二羟基-1 H-苯并[d]咪唑作为 JNK3 抑制剂，并发现它们具有作为神经保护剂的潜力。在先前的先导支架之后，苯并咪唑部分被各种芳基和羟基化修饰，所得化合物表现出 JNK3 抑制活性，并具有更高的效力和选择性。在合成的 37 个类似物中，( S )-环丙基(3-((4-(2-(2,3-二氢苯并[b][ ¹, ⁴ ]二恶英-6-基)-5,6-二羟基-1H-苯并[d]咪唑-1-基)嘧啶-2-基)氨基)哌啶-1-基)甲酮( 35b )表现出最高的JNK3抑制 (IC ₅₀ = 9.7 nM)，以及对 Aβ 诱导的神经元细胞死亡的神经保护作用。作为一种蛋白激酶抑制剂，它还表现出优于其他蛋白激酶的选择性，包​​括同种型 JNK1（>1000 倍）和 JNK2（–10 倍）。