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 circulatory shock, Inotek Corporation is in the process of the development of mercaptoalkylguanidines for the experimental therapy of circulatory shock. Inotek is now also developing a """"""""second generation"""""""" class of iNOS inhibitor/peroxynitrite scavenger compounds, exemplified by the compounds 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, selenoguanidines maintain their iNOS inhibitory effects.
The first aim of the current study is to synthesize selenoethylguanidine (SEG), 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 SEG in a rat model of endotoxic shock, 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 cardiovascular chock is over $20 billion in the US alone.
