Department of Organic Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, P.R. China.
Curr Med Chem. 2013;20(15):1997-2016. doi: 10.2174/0929867311320150006.
Rheumatoid arthritis (RA) and other chronic inflammatory diseases are always the major therapeutic challenges. Recent research efforts provided new insights into the molecular basis of these diseases and new opportunities for developing improved anti-inflammatory drugs. The p38 mitogen-activated protein (MAP) kinase plays a central role in the regulation of the biosynthesis and release of several proinflammatory cytokines including tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β). Hence, inhibition of the p38 MAP kinase is regarded as a promising therapeutic strategy for controlling inflammatory diseases. A diverse range of p38α MAP kinase inhibitors have been developed as potential anti-inflammatory agents, and some of them have entered the phase II clinical trials. The imidazole derivatives are known as competitive inhibitors at the ATP binding site of the p38α MAP kinase. Modifications on the imidazole scaffold have led to a large amount of potent p38α MAP kinase inhibitors. This review will summarize the developments of small molecule p38α MAP kinase inhibitors based on the imidazole core scaffolds in recent 10 years. Variations at the N1, C2, C4 and C5 positions of imidazole were introduced, and the structure-activity relationships of these imidazole inhibitors were also discussed.
类风湿性关节炎（RA）和其他慢性炎症性疾病一直是主要的治疗挑战。最近的研究努力为这些疾病的分子基础提供了新的见解，并为开发改进的抗炎药物提供了新的机会。p38 丝裂原活化蛋白（MAP）激酶在调节几种促炎细胞因子（包括肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β））的生物合成和释放中起着核心作用。因此，抑制 p38 MAP 激酶被认为是控制炎症性疾病的一种有前途的治疗策略。已经开发了多种 p38α MAP 激酶抑制剂作为潜在的抗炎剂，其中一些已进入 II 期临床试验。咪唑衍生物是已知的 p38α MAP 激酶 ATP 结合位点的竞争性抑制剂。咪唑骨架上的修饰导致了大量有效的 p38α MAP 激酶抑制剂。这篇综述将总结过去 10 年基于咪唑核心骨架的小分子 p38α MAP 激酶抑制剂的发展。介绍了咪唑的 N1、C2、C4 和 C5 位置的变化，并讨论了这些咪唑抑制剂的构效关系。
