Intramolecular Hydrogen-Bonded Nitric Oxide Synthase Inhibitors

Neuronal Nitric Oxide Synthase Inhibitors that Permeate the Blood-Brain Barrier for Treatment of Neurodegenerative Diseases NU 2010-075 Inventors Richard B. Silverman* Fengtian Xue Short Description A series of potent neuronal nitric oxide synthase inhibitors that permeate the blood-brain barrier for treatment of neurodegenerative disorders Abstract Neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases, affect millions of Americans. Hundreds of billions of dollars are spent annually to treat and care for patients with these generally incurable conditions. There is an urgent need for development of effective therapies for neurodegenerative disease. A key pathogenic phenomenon observed in a variety of these diseases is increased concentration of cerebral nitric oxide (NO). As a result, the neuronal isoform of nitric oxide synthase (nNOS) has been a target for therapy development. A major difficulty of identifying an appropriate drug agent for inhibition of this enzyme is the requirement for the molecule to cross the blood-brain barrier. Attempts to modify inhibitors to improve transmission across the barrier have resulted in decreased potency. Northwestern researchers have designed and synthesized a series of nNOS inhibitors that adopt a "closed" conformation in hydrophobic environments, but an "open" position when bound to nNOS. These alternate positions allow the molecules to cross the fatty blood-brain barrier but expose the pharmacologically active residues when in contact with nNOS, maintaining potency while overcoming the obstacle of permeability. These inhibitors can have far-reaching effects on neurodegenerative disease treatment. Applications o Treatment of neurodegenerative disorders such as Alzheimer's, Parkinson's, Huntington's, headache, and damage due to stroke Advantages o Improved movement across blood-brain barrier o Maintained potency o Useful for a variety of conditions IP Status A patent application has been filed. Marketing Contact Allan Nader, PhD Invention Manager (e) [email protected] (p) 847.491.4456