This grant builds upon the research from a prior grant: Optimizing Metalloporphryins for Clinical Development
Promising Outcomes of Original Grant:
The overall goal of this ongoing proposal is to determine if a newly developed series of metalloporphyrins designed to penetrate blood brain barrier shows promise for treatment of Parkinson’s disease. The goal of the original NADD award was to determine the pharmacokinetic profiles, efficacy and potential adverse effects of several lead lipid soluble metalloporphyrin catalytic antioxidants. The results of this study indicated that a subset of the tested compounds showed unfavorable bioavailability which led to the evaluation of addition novel compounds in this series. Preliminary data suggest favorable bioavailability and in vivo efficacy of a subset of the new compound.
Objectives for Supplemental Investigation:
Oxidative stress is a well-defined therapeutic target for Parkinson’s disease (PD) and pharmacological agents that catalytically scavenge reactive species are promising neuroprotective strategies for its treatment. Metalloporphyrins are synthetic catalytic antioxidants that mimic the body’s own antioxidant defensive enzymes i.e. superoxide dismutases and catalase. The ongoing goal of this proposal is to determine if a newly developed lipophilic metalloporphyrins designed to penetrate blood brain barrier shows promise for treatment of PD. The specific goal of the supplemental award is to further optimize the structures of promising novel metalloporphyrins and subsequently evaluate their bioavailability, in vivo efficacy and potential for adverse effects.
Importance of This Research for the Development of a New PD Therapy:
Current therapeutic approaches to treat PD are associated with serious adverse effects and fail to provide long-term control this inexorably progressive disease. Therefore, there is an urgent need for novel classes of therapeutic agents for the treatment of PD. This project can rapidly identify an orally active compound for the treatment of PD.
Final Outcome
Oxidative stress is a well-defined therapeutic target for Parkinson’s disease (PD) and pharmacological agents that catalytically scavenge reactive species are promising neuroprotective strategies for its treatment. Metalloporphyrins are synthetic catalytic antioxidants that mimic the body’s own antioxidant defensive enzymes i.e. superoxide dismutases and catalase. The goal of this proposal was to determine if a newly developed lipophilic metalloporphyrins designed to penetrate blood brain barrier shows promise for treatment of PD. During this award period we have optimized the structures of promising novel metalloporphyrins and subsequently evaluated their bioavailability, in vivo efficacy and potential for adverse effects in pre-clinical models. Our results identified three compounds in this series with promising oral bioavailability and pre-clinical efficacy.
PARTNERING PROGRAM
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation’s Partnering Program.