Hashimoto Y
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
Curr Med Chem. 1998 Jun;5(3):163-78.
Thalidomide (N-alpha-phthalimidoglutarimide) was used widely as a hypnotic/sedative agent in the late 1950s and the early 1960s, but had to be withdrawn from the market because of its severe teratogenicity. In spite of this, there has been a resurgence of interest in the drug in recent years due to its potential usefulness for the treatment of various diseases, including acquired immunodeficiency syndrome (AIDS) and graft-versus-host disease (GVHD). The effectiveness of the drug in these diseases has been attributed to its specific inhibitory activity on tumor necrosis factor-alpha (TNF-alpha) production. Because TNF-alpha, a cytokine mediating host defence and immune regulation, with a wide range of activities, has deleterious pathophysiological effects in various diseases, including AIDS, tumors, rheumatoid arthritis and diabetes, its production-regulators are attractive lead compounds for novel biological response modifiers. The regulatory effect of thalidomide on TNF-alpha production has been found to be bidirectional, depending on both the cell-type and the TNF-alpha production-inducer; i.e., thalidomide possesses both enhancing and inhibiting activities on TNF-alpha production. Structural modification of thalidomide aiming at the creation of superior TNF-alpha production-regulators has afforded a number of phenyl- and benzylphthalimide analogs possessing more potent activity than thalidomide itself. The structure-activity relationships of these analogs has been investigated. The bidirectional TNF-alpha production-regulating activity is electronic state- and enantio-dependent, and both pure inhibitors and pure enhancers of TNF-alpha production has been obtained. Further structural development of the phthalimide analogs has yielded potent non-steroidal androgen antagonists.
沙利度胺（N-α-邻苯二甲酰亚氨基戊二酰亚胺）在20世纪50年代末和60年代初被广泛用作催眠/镇静剂，但由于其严重的致畸性而不得不退出市场。尽管如此，近年来人们对该药物的兴趣再度兴起，因为它在治疗包括获得性免疫缺陷综合征（艾滋病）和移植物抗宿主病（GVHD）在内的各种疾病方面具有潜在用途。该药物在这些疾病中的有效性归因于其对肿瘤坏死因子-α（TNF-α）产生的特异性抑制活性。由于TNF-α是一种介导宿主防御和免疫调节的细胞因子，具有广泛的活性，在包括艾滋病、肿瘤、类风湿性关节炎和糖尿病在内的各种疾病中具有有害的病理生理作用，因此其产生调节剂是新型生物反应调节剂的有吸引力的先导化合物。已发现沙利度胺对TNF-α产生的调节作用是双向的，这取决于细胞类型和TNF-α产生诱导剂；即，沙利度胺对TNF-α产生具有增强和抑制活性。旨在创造更优异的TNF-α产生调节剂的沙利度胺结构修饰已产生了许多比沙利度胺本身具有更强活性的苯基和苄基邻苯二甲酰亚胺类似物。已对这些类似物的构效关系进行了研究。双向TNF-α产生调节活性是电子状态和对映体依赖性的，并且已获得了TNF-α产生的纯抑制剂和纯增强剂。邻苯二甲酰亚胺类似物的进一步结构开发已产生了有效的非甾体雄激素拮抗剂。
