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Abstract
Grant Number: 5R44NS039216-03 PI Name: SZABO, CSABA PI Email: szabocsaba@aol.com PI Title: VICE PRESIDENT FOR RESEARCH Project Title: Peroxynitrate neutralizing agents for stroke therapy Abstract: 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.
Thesaurus Terms:
cardiovascular disorder chemotherapy, drug design /synthesis /production, peroxynitrite, stroke, stroke therapy
cytotoxicity, disease /disorder model, dosage, drug discovery /isolation, drug screening /evaluation, free radical scavenger, guanosine monophosphate, nitric oxide, nitric oxide synthase, pharmacokinetics, reperfusion
laboratory rat
Institution: INOTEK PHARMACEUTICALS CORPORATION 100 CUMMINGS CTR, STE 419E BEVERLY, MA 01915 Fiscal Year: 2003 Department: Project Start: 06-SEP-1999 Project End: 31-AUG-2004 ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE IRG: ZRG1