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Development of Phthalimide-type Novel Tumor Necrosis Factor (TNF) Production-regulators

邻苯二甲酰亚胺型新型肿瘤坏死因子（TNF）产生调节剂的开发

基本信息

批准号：
07457548
负责人：
HASHIMOTO Yuichi
金额：
$ 4.03万
依托单位：
THE UNIVERSITY OF TOKYO
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

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was used widely as a hypnotic/sedative agent in the late 1950s and the early 1960s, but had to be withdrawn from the market because of its severe teratogenicity.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 deseases, including acquired immunodeficiency syndrome (AIDS), leprosy, malaria, and graft-versus-host desease (GVHD). It has been also attracting attention because of its efficient antiangiogenetic activity. The effectiveness of the drug in these deseases has been attributed to its specific inhibitory activity on tumor necrosis factor (TNF), -alpha production. Because TNF-alpha, a cytokine medating host defense and immune regulation, with a wide range of activities, has deletorious pathophysiological effects in various deseases, including AIDS,tumors, theumatoid arthritis, and diabetes, its production-regulators are are attracative lead … More 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 a afforded a number of pheny1- 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 potent inhibitors and pure potent enhancers of TNF-alpha production has been obatined. Further structural development of the phthalimide analogs has yielded potent non-steroidal androgen antagonists (much more potent than flutamide) and potent aminopeptidase N-inhibitors (more potent than bestatin). Less

沙利度胺（N-α-邻苯二甲酰亚胺戊二酰亚胺）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，近年来由于其对治疗各种疾病，包括获得性免疫缺陷综合征（AIDS）、麻风病、疟疾和移植物抗宿主病（GVHD）的潜在有用性，对该药物的兴趣重新抬头。由于其有效的抗血管生成活性也引起了人们的关注。该药物在这些疾病中的有效性归因于其对肿瘤坏死因子（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，在艾滋病、肿瘤、风湿性关节炎和糖尿病等多种疾病中具有良好的病理生理作用，因此其产生调节剂是一个非常有吸引力的研究热点 ...更多信息用于新型生物反应调节剂的化合物。已经发现沙利度胺对TNF-α产生的调节作用是双向的，取决于细胞类型和TNF-α产生诱导剂;即，沙利度胺对TNF-α的产生具有增强和抑制活性。旨在产生上级TNF-α产生调节剂的沙利度胺的结构修饰已经提供了许多具有比沙利度胺本身更有效活性的苯基和苄基邻苯二甲酰亚胺类似物。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，并且已经获得了TNF-α产生的纯有效抑制剂和纯有效增强剂。邻苯二甲酰亚胺类似物的进一步结构开发产生了有效的非甾体雄激素拮抗剂（比氟替卡松有效得多）和有效的氨肽酶N-抑制剂（比bestatin有效）。少