Abstract：
CK1δ is a serine-threonine kinase involved in several pathological conditions including neuroinflammation and neurodegenerative disorders like Alzheimer\'s disease, Parkinson\'s disease, and Amyotrophic Lateral Sclerosis. Specifically, it seems that an inhibition of CK1δ could have a neuroprotective effect in these conditions. Here, a series of [1,2,4]triazolo[1,5-a][1,3,5]triazines were developed as ATP-competitive CK1δ inhibitors. Both positions 2 and 5 have been explored leading to a total of ten compounds exhibiting IC50s comprised between 29.1 µM and 2.08 µM. Three of the four most potent compounds (IC50 < 3 µM) bear a thiophene ring at the 2 position. All compounds have been submitted to computational studies that identified the chain composed of at least 2 atoms (e.g., nitrogen and carbon atoms) at the 5 position as crucial to determine a key bidentate hydrogen bond with Leu85 of CK1δ. Most potent compounds have been tested in vitro, resulting passively permeable to the blood-brain barrier and, safe and slight neuroprotective on a neuronal cell model. These results encourage to further structural optimize the series to obtain more potent CK1δ inhibitors as possible neuroprotective agents to be tested on models of the above-mentioned neurodegenerative diseases.
摘要：
CK1δ是一种丝氨酸-苏氨酸激酶，参与多种病理状况，包括神经炎症和神经退行性疾病，如阿尔茨海默病，帕金森病,和肌萎缩侧索硬化症.具体来说,在这些情况下，抑制CK1δ似乎具有神经保护作用。这里,开发了一系列[1,2,4]三唑并[1,5-a][1,3,5]三嗪作为ATP竞争性CK1δ抑制剂。位置2和5都已被探索,导致总共10种化合物表现出包含在29.1μM和2.08μM之间的IC50。四种最有效的化合物中的三种（IC50<3μM）在2位带有噻吩环。所有化合物都已提交计算研究，确定了由至少2个原子组成的链（例如，5位的氮和碳原子）对于确定与CK1δ的Leu85的关键双齿氢键至关重要。大多数有效的化合物已经过体外测试，导致血脑屏障被动渗透，在神经元细胞模型上安全和轻微的神经保护。这些结果鼓励进一步结构优化系列以获得更有效的CK1δ抑制剂作为在上述神经退行性疾病模型上测试的可能的神经保护剂。
