Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
ChemMedChem. 2010 Jul 5;5(7):1134-42. doi: 10.1002/cmdc.201000114.
The p38 mitogen-activated protein (MAP) kinase alpha plays a central role in the regulation of cellular responses such as differentiation, proliferation, apoptosis, and inflammation. Inhibition of p38 results in decreased synthesis of pro-inflammatory cytokines. To date, diverse p38alpha inhibitors are in phase II clinical trials for numerous cytokine-dependent diseases. 2-Sulfanylimidazole derivatives offer advantages over the prototype inhibitor SB 203580, including fewer cytochrome P450 interactions and better kinetic properties. The aim of this study was to develop novel 1,2,4,5-tetrasubstituted pyridinylimidazoles with acyl residues at the imidazole N1 position that can interact with the kinase's hydrophobic region II (HR II) or sugar pocket (SP) to improve both selectivity and activity. The substitution pattern was optimized by variation of the acyl moiety at the N1 position of the N-aminoimidazole core. Acylation of the amino function was used for optimization and led to potent p38alpha MAPK inhibitors.
p38 丝裂原活化蛋白（MAP）激酶α在细胞反应的调节中起着核心作用，如分化、增殖、凋亡和炎症。p38 的抑制导致促炎细胞因子的合成减少。迄今为止，多种 p38α 抑制剂正在进行针对许多细胞因子依赖性疾病的 II 期临床试验。2-硫代亚氨基咪唑衍生物与原型抑制剂 SB 203580 相比具有优势，包括更少的细胞色素 P450 相互作用和更好的动力学特性。本研究旨在开发新型 1,2,4,5-四取代吡啶基咪唑，其咪唑 N1 位置带有酰基残基，可与激酶的疏水区域 II（HR II）或糖口袋（SP）相互作用，以提高选择性和活性。通过改变 N-氨基咪唑核心的 N1 位置上的酰基部分来优化取代模式。酰化氨基功能用于优化，并导致有效的 p38αMAPK 抑制剂。
