PEROXYNITRATE NEUTRALIZING AGENTS FOR STROKE THERAPY

DESCRIPTION (provided by applicant):Nitric oxide (NO) and peroxynitrite are reactive, short-lived species that are important mediators of cellular injury in reperfusion injury associated with ischemic stroke. The applicants are developing novel classes of peroxynitrite neutrahzer compounds with protective effects in stroke. In this proposal, we present evidence that such agents are (1) inhibitors of cell injury triggered by various oxidants and free radicals (2) exert protective effects in a rat model of stroke . The specific aims of the present proposal are the following: (1) to synthesize large quantities of SEGED as well as FP15 and FP16, members of the applicants' second generation peroxynitrite decomposition catalyst compounds, and perform extensive and definitive stroke studies with a wide range of dosing regimen and delayed administration. Additional aims of the current submission are (2) to perform in-house toxicity testing, to determine the therapeutic ratio of each of the compounds. Based on the outcome of (1) and (2), we will select a lead drug candidate for further, formal preclinical toxicity studies. The final aim of the current studies (3) is to perform pre-clinical pharmaceutical testing (advanced toxicity determinations, pathology, stability, pharmacokinetics, in vivo efficacy), in order to reach the stage of investigational drug application to the FDA and Phase 1 clinical trial with the lead peroxynitrite decompositton catalyst for the treatment of isehem c stroke.