Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors with Improved Membrane Permeability

Highly Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors with Improved Membrane Permeability NU 2008-172 Inventors Richard Silverman* Fengtian Xue Short Description Synthesis of a series of compounds with increased selective inhibition of neuronal nitric oxide synthase (nNOS) and with improved membrane permeability Abstract Northwestern researchers have isolated and identified a series of compounds that have significant implications in the treatment of neurological diseases. The family of NOS enzymes, of which there are three principal isoforms, biosynthesize an important biological second messenger called nitric oxide. While inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) are crucial for maintaining body function, the activity of neuronal nitric oxide synthase (nNOS) has become a desired target for control as its overexpression has been implicated in various neurological diseases and neuronal damage. While new peptidomimetic compositions exhibit excellent inhibitory potency and selectivity for nNOS over eNOS and iNOS, their bioavailability has limited their therapeutic potential. This invention creates new structural motifs based on NOS enzyme crystal model and active domain studies. A series of unique molecules were identified providing candidates with excellent nNOS selectivity and potency. Enhanced bioavailability was achieved by exploring the charge and pKa properties of the candidate inhibitors. Isolation of individual inhibitor enantiomers identified significant activity and selectivity differences from the racemic inhibitors. These results provide a potent family of nNOS inhibitor compositions with promising bioavailability for therapeutic use. Applications Therapeutics for neurological disorders: Stroke, Schizophrenia, Migraine Headaches, Cerebral Ischemia, Long-Term Depression, Parkinson's disease and Alzheimer's disease Advantages Increased selective modulation of nitric oxide synthesis Long-term management of neurological disorders Increased potency Enhanced bioavailability IP Status Issued US Patent No. 7,470,790 Contact Information Allan Nader, PhD Invention Manager (p) (847) 491-4456 (e) a-nader@northwestern.edu