Development of MX-4565, a Novel Estrogen Analogue, for the Treatment of Parkinson's Disease

Objective/Rationale: 
MX-4565 is a compound that is highly potent in protecting nerve cells from death in a number of cell culture and animal models systems.  For example, it has been shown to provide complete protection of nerve cells in the brain in a rodent model of Parkinson’s Disease (PD).  The next step in the development of MX-4565 is to determine how it can be administered most effectively as a drug (orally, subcutaneously, etc.).

Project Description: 
The first set of experiments will involve dosing mice with MX-4565 by different routes of administration (orally, intravenously, and subcutaneously).  Blood samples will be taken at various time points and the concentration of MX-4565 determined.  Analysis of this type (termed pharmacokinetics or PK) provides valuable information on how quickly and how effectively the compound is taken up in the body and how long it remains there.  It is important to determine how effectively MX-4565 is taken up when delivered orally and subcutaneously, as these are the most common routes of drug administration.  If MX-4565 is readily available orally, modeling and multi-dose studies will be performed to predict optimal dosing in PD patients.  Alternatively, if MX-4565 has poor oral bioavailability, then PK analysis of MX-4565 in extended-release subcutaneous pellets will be carried out as a method of dosing.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:  
Pharmacokinetic analysis is an important step in the drug development process.  Once the PK analysis has been completed, we will be able to test MX-4565 in pivotal animal studies of PD, prior to formal preclinical development, using optimal dosing and route of administration.  In addition to its potent neuroprotection activity, MX-4565 is an estrogen analogue that is non-feminizing except at very high doses that would exceed therapeutic levels.  Thus, MX-4565 is very unlikely to have the side-effects that accompany long-term estrogen use in women and, furthermore, it can be used in male PD patients.

Anticipated Outcome: 
These experiments will provide key information for the development of MX-4565 as a potential treatment to slow the development of PD in patients.  Previous work has shown that MX-4565 is very effective at protecting nerve cells from toxic stresses.  These experiments will now tell us how best to administer the compound as a drug in animal models of PD.  This is a crucial step in the moving MX-4565 from the laboratory to the clinic.