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.
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