Poly(ADP-ribosyl)ation is an immediate cellular response to DNA damage and is catalyzed by poly(ADP-ribose) polymerase (PARP-1). Directly stimulated by DNA breaks, PARP-1 is involved in a variety of physiological and pathophysiological phenomena. Physiologically it is important for maintaining genomic stability. Pathophysiologically, PARP-1 overactivity contributes to a number of diseases associated with cellular stress. Hence the development of PARP-1 inhibitors has represented a major pharmaceutical challenge. One particularly exciting therapeutic candidate, PJ34 has demonstrated wide-spread therapeutic activity. For example PJ34 demonstrated efficacy in numerous inflammatory models. In a model of systemic endotoxemia, PJ34 pretreatment significantly reduced plasma levels of TNF-alpha, IL-1beta and nitrite/nitrate production. PJ34 treatment also induced a significant suppression of the inflammatory response in models of colitis, autoimmune diabetes and uveitis. During hyperglycemic states nitrogen and oxygen species are produced that result in the endothelial dysfunctions underlying many complications associated with diabetes. Therefore it is of immense interest that PJ34 not only prevents the development of endothelial dysfunction in experimental diabetes but even more importantly, it rapidly reverse it. Likewise, PJ34 has also demonstrated therapeutic activity in a number of models of ischemia. Overactivation of PARP appears to be prominent in vascular stroke and other neurodegenerative diseases causing necrotic neural death. Not surprisingly therefore, PJ34 exerts a dramatic neuroprotective response in experimental stroke. Finally and most recently, PJ34 provides cardioprotection in a porcine model of myocardial ischemia-reperfusion injury. Thus the development of PARP-1 inhibitors such as PJ34 represents an advancing area of therapeutics. At present under 10 PARP-1 inhibitors are in development, although none have yet entered the clinic. Since this class has implications for a variety of serious diseases, most of which represent unmet markets, the further development of molecules such as PJ34 offers considerable clinical and financial promise.

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