Laufer Stefan A, Zimmermann Werner, Ruff Kathrin J
Department of Pharmacy, Institute of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
J Med Chem. 2004 Dec 2;47(25):6311-25. doi: 10.1021/jm0496584.
We prepared novel 1,2,4,5-tetrasubstituted imidazole derivatives with high anti-inflammatory activity by using our previously described regiospecific synthesis. Systematic optimization of the imidazole N-1 substituent resulted in compound 9b that potently inhibited the mitogen-activated protein kinase p38 (p38 IC(50) = 0.218 microM) as well as the release of the proinflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) from human whole blood after stimulation with LPS. Furthermore, compound 9b exhibited reduced cytochrome P450 interaction in comparison with SB203580. This result is particularly important, since cytochrome P450 interaction is observed for some p38 inhibitors and in turn can potentially cause drug-drug interaction or lead to other hepatic changes such as P450 enzyme induction.
我们通过之前描述的区域特异性合成方法制备了具有高抗炎活性的新型1,2,4,5-四取代咪唑衍生物。对咪唑N-1取代基进行系统优化得到了化合物9b，其能有效抑制丝裂原活化蛋白激酶p38（p38 IC(50) = 0.218 microM），以及脂多糖刺激后人全血中促炎细胞因子白细胞介素-1β（IL-1β）和肿瘤坏死因子α（TNFα）的释放。此外，与SB203580相比，化合物9b表现出降低的细胞色素P450相互作用。这一结果尤为重要，因为在一些p38抑制剂中观察到了细胞色素P450相互作用，进而可能导致药物相互作用或引发其他肝脏变化，如P450酶诱导。
