PHOSPHAZOLES--POTENT INHIBITORS OF TNF ALPHA PRODUCTION

描述：细胞因子，如肿瘤坏死因子-α和 白介素1β(IL-1β)在炎症中的作用 在人类包括肿瘤在内的许多疾病的发病过程中起着重要的作用。 能抑制肿瘤坏死因子α的产生和成熟的药物 IL-1β在这些适应症中可能具有极好的治疗潜力。 因此，这项研究的长期目标是开发药物来 威胁某些肿瘤、炎症和危及生命的休克。数据 在初步研究部分提出的这部小说确立了 磷唑7-氨基-1H-1，3-氮杂磷并[4，5-d]嘧啶(7)及其 衍生物是肿瘤坏死因子α、白介素1β和核因子-kB的有效抑制剂，具有 毒性最小。此应用程序的具体目标是验证 初步发现，合成了更多的磷唑类似物和 体外评价它们对细胞因子激活的抑制活性。 在小鼠足垫模型中测定无毒化合物的活性 炎症和内毒素诱导的感染性休克模型。也是 确定化合物7是否抑制肿瘤坏死因子依赖的磷酸化和 IKBα的降解，从而导致核因子-kB的p65亚单位易位 到原子核。从这些研究中发现的最有效的药物将 经历随后的临床前开发，包括看似合理的机制 的行动研究，特别强调肿瘤坏死因子依赖的抑制 核因子-kB及其对其他转录因子的影响 这个项目的第二部分。 建议的商业应用： 潜在的商业应用程序不可用。

DESCRIPTION: Cytokines such as tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1beta) have been implication in inflammatory processes and in pathogenesis of many diseases including tumors in human. Agents which can inhibit the production and maturation of TNF alpha and IL-1 beta in these indications may have excellent therapeutic potential. Therefore, the long-term objective of this research is to develop drugs to threat certain tumors, inflammation and life threatening shock. The data presented in the preliminary studies section established that the novel phosphazole 7-amino-1H-1,3-azaphospholo[4,5-d]pyrimidine (7) and its derivatives are potent inhibitors of TNF alpha, IL-1beta, and NF-kB with minimal toxicity. The specific aims of this application are to validate the preliminary findings, synthesize additional phosphazol analogs and evaluate their inhibitory activity of cytokine activation in vitro. Determine the activity of nontoxic compounds in a mouse footpad model of inflammation and in an endotoxin induced septic shock model. Also establish whether compound 7 inhibits TNF-dependent phosphorylation and degradation of IkB alpha and hence translocation of p65 subunit of NF-kB to the nucleus. The most effective agents emerging from these studies will undergo subsequent preclinical development including plausible mechanism of action studies with particular emphasis on TNF DEPENDENT INHIBITION OF NF-kB as well as their effect on other transcription factors during Phase II of this project. PROPOSED COMMERCIAL APPLICATION: Potential commercial application not available.