In recent studies, our group have presented evidence that mercaptoethylguanidine (MEG) and related agents such as its dimeric form guanidinoethyldisulfide (GED) are promising inducible nitric oxide synthase (iNOS) inhibitors with selectivity for the inducible isoform (iNOS). In addition, we have obtained data, which demonstrated that these compounds are scavengers of the cytotoxic oxidant peroxynitrite. Based on the role NO and peroxynitrite plays in the pathogenesis of periodontal disease, we are currently developing a first-generation candidate of the MEG class for periodontal diseases. Recent in vivo data demonstrated that MEG and GED are effective in suppressing the course of inflammation in the ligature-induced gingivitis/periodontitis model in the rat. Furthermore, we present data demonstrating the appropriate therapeutic ratio of MEG and GED. Inotek Corporation is in the process of the development of mercaptoalkylguanidines for the experimental therapy of periodontal disease. Inotek is now also developing a """"""""second generation"""""""" class of iNOS inhibitor/peroxynitrite scavenger compounds, exemplified by selenoethylguanidine and selenopropylguanidine. Preliminary in vitro data suggest that substitution of the sulfur group to selenium increases the reactivity of the compound with peroxynitrite by about 100-fold. In addition, selenoethylguanidine maintains its iNOS inhibitory effects.
The first aim of the current study is to synthesize selenoguanidines, and perform in vitro studies to characterize its effects as NOS inhibitor, determine their isoform selectivity, and their peroxynitrite scavenging activity.
The second aim of the study is to test selenoguanidines in a rat model of periodontal disease, where NO and peroxynitrite play a key role in disease development. The results of the present application will permit application for Phase 2 SBIR funding to support: pre-clinical pharmaceutical testing (further testing in animal models, advanced toxicity determinations, pathology, stability, pharmacokinetics, in vivo efficacy), IND application to the FDA, and Phase 1 clinical trial).
The annual anticipated revenues for an effective therapeutic to prevent and treat periodontal disease is over $30 billion in the US alone.
| Lohinai, Z; Mabley, J G; Feher, E et al. (2003) Role of the activation of the nuclear enzyme poly(ADP-ribose) polymerase in the pathogenesis of periodontitis. J Dent Res 82:987-92 |
