PHOSPHAZOLES--POTENT INHIBITORS OF TNF ALPHA PRODUCTION

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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.