Core--Development and analysis of SOD/Catalase mimetics

这一科学核心将提供药物发现和制药研究和开发专业知识，特别是在合成SOD/过氧化氢酶模拟物方面。这种由核心研究所开发的化合物已经在几种形式的慢性辐射诱导损伤的动物模型中显示出有效性。研究项目将进一步研究这些化合物在减轻和治疗辐射损伤方面的潜在价值。该中心将为研究项目提供人工合成的超氧化物歧化酶/过氧化氢酶模拟物，以作为辐射缓减和治疗剂进行评估，分析组织和血浆中化合物的水平，并总的来说， 帮助开发优化的化合物和剂量方案，以用作全身放射缓解或治疗剂。被研究项目确定为特别有希望的化合物和剂量方案将被考虑作为辐射缓解和/或治疗剂用于临床开发。为了促进这一过程，中心将进行某些必要的活动，以选择一种用于临床开发的铅超氧化物歧化酶/过氧化氢酶模拟物。有了铅化合物，核心将与项目调查人员合作，实施提交IND所需的初步研究，包括为GLP项目辐射防护研究提供GMP级材料。这一核心的具体专业领域将包括：(1)化合物的设计和由合同实验室监督其合成；(2)从化合物的化学、催化、体外细胞保护和关键物理性质方面筛选和表征化合物；(3)从生物样本(组织、血浆等)中提取和分析化合物和代谢物。提供药代动力学和药效学信息；(4)为候选药物开发临床相关剂量和处方方法 先导化合物(S)；(5)药物开发活动(包括cGMP的制造和药材的稳定性分析)。核心内部的监管专业知识也将用于就其设施和研究的GLP合规性向计划调查人员提供建议。 这些化合物代表了一种治疗可能由放射性恐怖主义事件造成的那种辐射损伤的新方法。这个核心将使这些化合物可用于在项目1、2、4和5中使用的真实正常组织损伤模型中进行测试。

This Scientific Core will provide drug discovery and pharmaceutical research and development expertise, in particular with regard to synthetic SOD/catalase mimetics. Such compounds, developed by the Core Institution, have shown efficacy in animal models for several forms of chronic radiation-induced injury. The Research Projects will further examine the potential value of these compounds for the mitigation and treatment of radiation injuries. The Core will serve the Research Projects by providing synthetic SOD/catalase mimetics for evaluation as radiation mitigation and treatment agents, analyzing tissue and plasma levels of compounds, and, overall, helping to develop compounds and dosing regimens optimized for use as systemic radiation mitigation or treatment agents. Compounds and dosing regimens identified as particularly promising by the Research Projects will be considered for clinical development as a radiation mitigation and/or treatment agent. To facilitate this process, the Core will conduct certain activities necessary to select a lead SOD/catalase mimetic for clinical development. With a lead compound in hand, the Core will implement, in collaboration with Project investigators, the initial research necessary for filing an IND, including supply of GMP grade material for Project GLP radiation protection studies. Specific areas of expertise of this Core will include: (1) Design of compounds and oversight of their synthesis by a contract laboratory; (2) Screening and characterization of compounds with respect to their chemical, catalytic, in vitro cytoprotective and key physical properties; (3) Extraction and analysis of compounds and metabolites from biological samples (tissues, plasma, etc.) to provide pharmacokinetic and pharmacodynamic information; (4) Developing clinically relevant dosing and formulation methods for candidate lead compound(s); and (5) Drug development activities (including cGMP manufacture and stability analysis of drug substance). The regulatory expertise within the Core will also be available to advise Program investigators on GLP compliance for their facilities and studies. These compounds represent a novel approach to the treatment of radiation injuries of the kind that might be caused by radiological terrorism events. This core will serve to make those compounds available for testing in the realistic normal tissue injury models used in Projects 1 ,2, 4 and 5.