Peifer Christian, Wagner Gerd, Laufer Stefan
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Curr Top Med Chem. 2006;6(2):113-49. doi: 10.2174/156802606775270323.
The therapy of chronic inflammatory diseases like rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) has recently been enriched by the successful launch of the anti-cytokine biologicals Etanercept (tumor necrosis factor (TNF) receptor-p75 Fc fusion protein), Infliximab (chimeric anti-human TNF-alpha monoclonal antibody), Adalimumab (recombinant human anti-human TNF-alpha monoclonal antibody) and Anakinra (recombinant form of human interleukin 1beta (IL-1) receptor antagonist). The success of these novel treatments has impressively demonstrated the clinical benefit that can be gained from therapeutic intervention in cytokine signalling, highlighting the central role of proinflammatory cytokine systems like IL-1alpha and TNF-alpha to be validated targets. However, all of the anti-cytokine biologicals available to date are proteins, and therefore suffering to a varying degree from the general disadvantages associated with protein drugs. Therefore, small molecular, orally active anti-cytokine agents, which target specific pathways of proinflammatory cytokines, would offer an attractive alternative to anti-cytokine biologicals. A number of molecular targets have been identified for the development of such small molecular agents but p38 mitogen-activated protein (MAP) kinase occupies a central role in the regulation of IL-1beta and TNF-alpha signalling network at both the transcriptional and translational level. Since the mid-1990s, an immense number of inhibitors of p38 MAP kinase has been characterised in vitro, and to date several compounds have been advanced into clinical trials. This review will highlight the correlation between effective inhibition of p38 MAP kinase at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-alpha and IL-1beta production. SAR will be discussed regarding activity at the enzyme target, but also with regard to properties required for efficient in vitro and in vivo activity.
类风湿关节炎（RA）和炎症性肠病（IBD）等慢性炎症性疾病的治疗，因抗细胞因子生物制剂依那西普（肿瘤坏死因子（TNF）受体 - p75 Fc融合蛋白）、英夫利昔单抗（嵌合抗人TNF - α单克隆抗体）、阿达木单抗（重组人抗人TNF - α单克隆抗体）和阿那白滞素（人白细胞介素1β（IL - 1）受体拮抗剂的重组形式）的成功上市而得到了丰富。这些新型治疗方法的成功令人印象深刻地证明了，通过对细胞因子信号传导进行治疗干预可获得临床益处，突出了促炎细胞因子系统如IL - 1α和TNF - α作为已得到验证的靶点的核心作用。然而，迄今为止所有可用的抗细胞因子生物制剂都是蛋白质，因此在不同程度上都存在与蛋白质药物相关的普遍缺点。因此，靶向促炎细胞因子特定途径的小分子口服活性抗细胞因子药物，将为抗细胞因子生物制剂提供有吸引力的替代方案。已经确定了许多用于开发此类小分子药物的分子靶点，但p38丝裂原活化蛋白（MAP）激酶在转录和翻译水平上对IL - 1β和TNF - α信号网络的调节中起着核心作用。自20世纪90年代中期以来，大量p38 MAP激酶抑制剂已在体外得到表征，迄今为止已有几种化合物进入临床试验。本综述将重点介绍在分子靶点上有效抑制p38 MAP激酶与细胞因子功能测定中的细胞活性之间的相关性，特别是TNF - α和IL - 1β的产生。将讨论关于酶靶点活性的构效关系，以及有效体外和体内活性所需的性质。
