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Abstract

Grant Number: 2R44DE013625-02A1
PI Name: SZABO, CSABA
PI Email: szabocsaba@aol.com
PI Title: VICE PRESIDENT FOR RESEARCH
Project Title: Novel antioxidants for periodontal disease

Abstract: DESCRIPTION: (provided by the applicant) The current application represents the first revision of a Phase 2 continuation of the Phase I NIH SBIR Grant 1 R43 DE13625 entitled "A novel agent for the therapy of gingivitis". The applicants are leaders in the research and preclinical development of novel, nitric oxide based innovative technologies for the development of periodontal disease. In the Phase I application, we have presented evidence that selenoethylguanidine (SEG) is a promising nitric oxide synthase (NOS) inhibitor with selectivity for the inducible nitric oxide synthase isoform (iNOS), and with an increased free radical scavenger activity, and proposed to perform pre-clinical studies in the rat to demonstrate its efficacy in gingivitis. The studies performed in the Phase I studies confirmed iNOS expression and peroxynitrite generation in periodontitis, and demonstrated the potent anti-inflammatory effects of SEG in a rat model of ligature-induced periodontitis. Further, we have demonstrated marked efficacy in the same experimental model with FP15, a novel peroxynitritie decomposition catalyst, and with PJ34, an inhibitor of the multifunctional nuclear enzyme poly(ADP-ribose) polymerase. These additional strategies specifically target NO-related downstream inflammatory pathways of periodontal inflammatory disease. In the current application, we propose to perform pre-clinical studies with SEG, FP15 and PJ34 in order to develop a lead candidate as treatments for gingivitis/periodontitis. The specific aims of the present proposal are to synthesize large quantities of the three test compounds, and perform studies in beagle dog models of gingivitis and periodontitis in order to obtain definitive proof of principle that the agents can reduce the tissue injury and inflammation. Based on the efficacy and safety data, a lead agent will be selected for further development for the experimental therapy of gingivitis and periodontitis. Additional aims of the current submission are to complete the pre-clinical pharmaceutical testing (GMP synthesis, advanced formulation, stability, and local irritation tests), to reach the stage of investigational drug application to the FDA. Throughout the work, Inotek Corporation collaborates with scientists at the University of North Carolina, a leading group in the experimental therapy of periodontal inflammation, as well as with leading contract research organizations to conduct GMP synthesis, formulation work and GLP animal safety testing.

Thesaurus Terms:
antioxidant, dental disorder chemotherapy, drug design /synthesis /production, enzyme inhibitor, gingiva disorder, guanidine, nonhuman therapy evaluation, periodontitis
drug screening /evaluation, pentosyltransferase, periodontium disorder, peroxynitrite, pharmacokinetics, selenated sulfur aminoacid
dog, high performance liquid chromatography, immunocytochemistry, liquid chromatography mass spectrometry, nuclear magnetic resonance spectroscopy

Institution: INOTEK PHARMACEUTICALS CORPORATION
100 CUMMINGS CTR, STE 419E
BEVERLY, MA 01915
Fiscal Year: 2003
Department:
Project Start: 15-SEP-2000
Project End: 30-JUN-2005
ICD: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
IRG: ZDE1


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