The objective for the proposed study is to determine the feasibility of using novel small molecule poly (ADP-ribose) polymerase (PARP) inhibitors as neuroprotective and cardioprotective agents to treat cardiac arrest patients for increased survival rate with improving prognosis in neurological and cardiac functions. Energy depletion due to over-activation of PARP has been found to cause neuronal and myocardial cell death during ischemia and reperfusion injuries. Inhibition of PARP, either by pharmacological inhibitors or gene deletion, has been proved an effective way to reduce infarct volumes in animal models of cerebral ischemia as well as regional heart ischemia. Guilford Pharmaceuticals Inc. has identified a series of water soluble PARP inhibitors that 1) achieved high level accumulation in plasma, heart and brain after intravenous dosing and 2) provided neuroprotection and cardioprotection in rat models of stroke and heart ischemia. We intend to test our proprietary PARP inhibitors in a well-established rat model of cardiac arrest. In collaboration with Dr. Daniel Hanley (the Johns Hopkins School of Medicine), we demonstrated that our leading PARP inhibitor, GPI 15427 significantly increased the survival rate with improved speed of recovery and neurological scores. To achieve the objective of the current study, we have designed a series of experiments that are aimed at 1) optimizing the chemical properties of GPI 15427 series compounds for """"""""drug like"""""""" properties; 2) characterizing the pharmacokinetic and toxicological profiles of GPI 15427 for better dosing regimen; and 3) determine the optimal dose-effect relationship of GPI 15427 series compounds in a rat model of cardiac arrest. We expect results from this phase I study will yield information for assessing the prospect of a phase II preclinical development towards clinical trials and commercialization of PARP inhibitors to treat cardiac arrest patients.
