A promising step on the road to developing new drugs for a variety of neurological diseases has been made by University of Notre Dame researchers. They were able to take this step by focusing on the design, synthesis and evaluation of water-soluble "gelatinase inhibitor" compounds.
Gelatinases, a class of enzymes, have been implicated in a host of human diseases from cancer to cardiovascular conditions and in particular neurological conditions such as stroke, aneurysm and traumatic brain injury.
The Notre Dame group has been investigating variants of a compound called "SB-3CT," which shows promise as a selective and potent gelatinase inhibitor.
The preferred method of treatment for acute gelatinase-dependent diseases is intravenous infusion. Intravenous administration requires that the compound be water-soluble.
Unfortunately SB-3CT has poor water solubility and poor drug-like properties.
In a new approach, the group from the University's Departments of Chemistry and Biochemistry and Biological Sciences and the Friemann Life Sciences Centre, used a prodrug strategy to address this issue.
A prodrug is an inactive precursor of a drug that is converted into its active form in the body by normal metabolic processes.
The prodrug strategy produced a greater than 5,000-fold increase in water solubility compared to SB-3CT.
In addition to its high water solubility, the prodrug (referred to as ND-478) was chemically stable, non-toxic and was quickly converted to the active drug in the blood.
These favourable properties of ND-478 make it suitable for intravenous administration in the treatment of acute gelatinase-dependent diseases.
Such a compound offers the possibility of translation into the clinic for treatment of strokes, aneurysms and traumatic brain injury.