Selective Inhibitors of Nitric Oxide Synthases (21036/98009)

This discovery presents two series of compounds that demonstrate very high selectivity for inhibition of neuronal nitric oxide synthase (nNOS) over the inducible nitric oxide synthase (iNOS) enzymes, crucial in the treatment of neurological diseased states. These inhibitors offer the potential for treatment of neurological disorders, including stroke, schizophrenia, migraine headaches, cerebral ischemia, long-term depression, Parkinson's, and Alzheimer's disease

ADVANTAGES: Selective modulation of the concentration of nitric oxide would allow long-term management of diseased states associated with excess nNOS formation.

SUMMARY: Nitric oxide is an important biological second messenger, which is biosynthesized by a family of enzymes called nitric oxide synthases, with three principal isoforms. The physiological activity associated with each of the nitric oxide synthases can be easily regulated by modulating the expression of each of the three isoforms. This discovery focuses on the identification of two series of compounds, which demonstrate very high selectivity for inhibition of neuronal nitric oxide synthase (nNOS) over the inducible nitric oxide synthase (iNOS). Of the Nω-substituted arginine analogues, Nω-propyl-L-arginine demonstrated significant selectivity for nNOS over both the inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS). A second series of compounds, dipeptides containing Nω-nitroarginine, also showed excellent selectivity. The unnatural D,D-isomer methyl esters or amides of dipeptides containing phenylalanine and nitroarginine are selective for nNOS over iNOS. The corresponding lysine and nitroarginine or ornithine and nitroarginine D,D-amides showed exceptional selectivity for nNOS over both iNOS and eNOS.

Crystal structures of the oxygenase domain of the three NOS isoforms explored with molecular design and modeling has provided another series of selective inhibitors promising enhanced bioavailability.

STATUS: A range of inhibitors have been synthesized, a patent has been granted and others filed Patent no. 6,274,557

Type of Offer: Licensing



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