Nitric oxide (NO) and peroxynitrite are reactive, short-lived species that are important mediators of cellular injury in reperfusion injury associated with ischemic stroke. Activation of poly (ADP- ribose) synthetase is one of the final common pathways of the NO/ peroxynitrite mediated excitotoxic neuronal injury in stroke. The applicants are developing a novel class of PARS inhibitor compounds with protective effects in stroke. In this proposal, we present evidence that the novel potent PARS inhibitor is (1) an inhibitor of cell injury triggered by various oxidants and free radicals (2) exerts protective effects in a murine model of stroke to an extent comparable to the protection seen in genetically engineered animals lacking functional PARS. The current application represents the Phase 2 continuation of the Phase I NIH SBIR Grant, entitled """"""""A novel PARS inhibitor for the therapy of stroke"""""""". In the current application, we propose to perform pre-clinical studies with a novel potent PARS inhibitor in order to develop it as a treatment for ischemic stroke. The first specific aim of the present proposal is to perform extensive studies in a second species (rat) with a wide range of doses and times of treatment relative to the beginning of the reperfusion. Additional aims of the current submission are to perform pre-clinical pharmaceutical testing (advanced toxicity determinations, pathology, stability, pharmacokinetics, in vivo efficacy), in order to reach the stage of investigational drug application to the FDA and Phase 1 clinical trial with a PARS inhibitor for the treatment of stroke. PROPOSED COMMERICAL APPLICATION 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. INH2BP may represent the first highly potent and successful candidate therapy; funding of SBIR Phase II will allow for market entry in 3 years.
| Komjati, Katalin; Mabley, John G; Virag, Laszlo et al. (2004) Poly(ADP-ribose) polymerase inhibition protect neurons and the white matter and regulates the translocation of apoptosis-inducing factor in stroke. Int J Mol Med 13:373-82 |
| Jagtap, Prakash; Soriano, Francisco Garcia; Virag, Laszlo et al. (2002) Novel phenanthridinone inhibitors of poly (adenosine 5'-diphosphate-ribose) synthetase: potent cytoprotective and antishock agents. Crit Care Med 30:1071-82 |
