Therapeutic hypothermia is currently the only clinically approved therapy to treat neurological injury across the central nervous system in the setting of cardiac arrest and other similar conditions, but it comes with a risk of adverse side effects. New therapies are desperately needed to restore normal brain function; however, compounds that inhibit activity of Pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPP) and promote AKT activity—the standard for neuroprotection in prior art—typically have limited ability to cross the blood brain barrier (BBB), a critical component for effectiveness, due to their chemical-structural property and high albumin binding. The BBB is a major obstacle in developing novel CNS-active small-molecule drugs, and thus, compounds that are expected to have neuroprotective abilities are unable to reach the locations where they are most needed.
Description
A thioketone compound NSC74429 has been identified as a potent neuroprotectant. Its neuroprotective abilities were demonstrated in three in vitro CNS injury models, including staurosporine, hydrogen peroxide, and glutamine excitotoxicity, and on two in vivo CNS injury models due to cardiac arrest and traumatic brain injury. Contrary to expectations, NSC74429 is not a PHLPP inhibitor, and does not activate AKT; rather, it inhibits AKT, a mechanism usually associated with cell death. The method by which NSC74429 works is still unknown, but it is safe to administer at therapeutic doses and has favorable predicted chemistry to efficiently cross the BBB. NSC74429 represents a new therapy with the potential to improve histological and neurological outcomes after a brain injury.
Applications
· Treatment of cellular injury
· Neuroprotection
Advantages
· Favorable chances of passing the blood brain barrier
· Treats cell death associated with both toxicity and traumatic injury
· Safe to administer at therapeutic doses without measurable side effects
Invention Readiness
In vivo data
IP Status
https://patents.google.com/patent/US20230105484A1
