Nitric oxide (NO) and peroxynitrite are reactive, short-lived species that are important mediators of various forms of inflammation and reperfusion injury. Recent studies have implicated the crucial role of NO and peroxynitrite in the pathogenesis of various forms of reperfusion, including stroke. Inotek Corporation has been developing various guanidine-based technologies for the treatment of various forms of inflammation and reperfusion injury. One of Inotek's prototype compounds, mercaptoethylguanidine (MEG) which is a selective inhibitor of the inducible nitric oxide synthase and scavenger of peroxynitrite, demonstrated efficacy in a variety of models of inflammation. As a next generation of guanidines, Inotek proposes to prepare and test selenoethylguanidine. Preliminary in vitro data demonstrated that substitution of the sulfur group by selenium increases the reactivity of the compound with peroxynitrite by about 100-fold. In addition, selenoethylguanidine maintains its NOS inhibitory effects.
The first aim of the current study is to synthesize selenoethylguanidine, and perform in vitro studies to characterize its effects as NOS inhibitor, determine its isoform selectivity, and its peroxynitrite scavenging activity.
The second aim of the study is to test selenoethylguanidine in a rat model of stroke, where peroxynitrite is known to play a key role in neuronal necrosis and apoptosis during the phase of reperfusion.
Worldwide the market for an effective, safe anti-stroke pharmaceutical is estimated to be 20 billion dollars per year, based upon 2 million patients at 10,000 dollars per treatment course. The demand for effective treatment of stroke is expected to increase steadily over the next 15 years. Current market entrants are marginally effective.
