Objective/Rationale:
Oxidative stress is a well-defined therapeutic target for Parkinson’s disease (PD) and antioxidant therapy is one of the most 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 is to determine if a newly developed glyoxylate (AEOL112) series of metalloporphyrins designed to penetrate blood brain barrier shows promise for treatment of PD.
Project Description:
A newly developed glyoxylate series of metalloporphyrin compounds designed to penetrate the blood brain barrier have shown high potencies as antioxidants. Studies in our laboratory have shown that several lead compounds in this series possess potent antioxidant properties. We recently showed that oral administration of one such compound (AEOL11207) protected dopaminergic neurons in a pre-clinical model of parkinsonism. This suggests the potential utility of glyoxylate metalloporphyrins such as AEOL11207 as therapeutic agents in PD. To expedite clinical development of this class of compounds, the proposed studies will determine the several lead lipophilic metalloporphyrins show favorable pharmacokinetic profiles following oral administration as well as efficacy in a preclinical model of parkinsonism. Additionally, AEOL11207 and related compounds will be assessed for potential behavioral toxicity related to manganese accumulation. These studies will optimize glyoxylate class of metalloporphyrins to identify the best drug candidate for clinical development for PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Current therapeutic approaches to treat PD are associated with serious adverse effects and fail to provide long-term control of 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.
Anticipated Outcome:
This project will optimize glyoxylate class of metalloporphyrins to identify the best drug candidate for clinical development for PD. These studies will determine 1) the plasma and brain pharmacokinetic profiles of lead compounds, 2) their ability to protect dopaminergic neurons in the mouse MPTP model and 3) whether manganese accumulation from chronic dosing poses a risk for adverse behavioral effects.
Final Outcome
Oxidative stress is a well-defined therapeutic target for Parkinson’s disease (PD) and antioxidant therapy is one of the most 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 glyoxylate (AEOL112) series of metalloporphyrins designed to penetrate blood brain barrier shows promise for treatment of PD.
We recently showed that oral administration of one such compound (AEOL11207) protected dopaminergic neurons in a pre-clinical model of parkinsonism. This suggests the potential utility of metalloporphyrins such as AEOL11207 as therapeutic agents in PD. In order to expedite clinical development of this class of compounds, we evaluated additional compounds in this class to identify the best drug candidate for clinical development for PD. These studies determined 1) the plasma and brain pharmacokinetic profiles of several lead compounds and 2) their ability to ameliorate MPTP neurotoxicity in a pre-clinical model. The data so far indicate favorable bioavailability and efficacy of this class of compounds in the pre-clinical setting suggesting their potential utility for clinical development.