An Introduction to NO-related Therapeutic Agents

Gregory   R.J.   Thatcher

Abstract

Investigational NO-related therapeutic agents span the range from prodrugs that elevate NO levels, to scavengers of NO, and inhibitors of endogenous NO synthesis. Related agents that influence nitrogen oxides, in addition to NO itself, are also to be considered. Organic nitrates have been used for over 130 years in cardiovascular therapy and hybrid nitrates continue to lead the way in clinical development for an increasing range of disease states. Selectivity for inhibition of NO synthase (NOS) isoforms is a continuing goal. Conversely, N-hydroxyarginine derivatives are substrates for NOS and represent a new NO donor class. Diazeniumdiolate (NONOate) NO donors have been essential for understanding of NO biology and are being developed as NO donor and HNO donor prodrugs including as photolabile sources. N-Hydroxyurea has been used as a cancer drug for decades and is approved for sickle cell disease treatment, but also provides a lead compound for design of NO and HNO donors. Nitroaliphatics and nitrosoaliphatics also represent chemical classes that include NO donors and exhibit biological activity that mimics that of NO. Nitroprusside has been in use since the 1920s and metal ion complexes continue to be explored, including as caged NO donors. Clear and exciting opportunities exist for new therapies based upon NO-related drugs. Despite the extensive clinical use of NO donor drugs and the role of NOS activation in the action of several prescription medications, challenges remain to the development of new NO-related therapeutics, but these are surmountable and are outweighed by the opportunities.

Keywords: scavengers, nitroxyl, nos inhibitors, soluble guanylyl cyclase, nitroxidation, inflammatory

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