Current Topics in Medicinal Chemistry - Volume 5, Issue 7, 2005

Despite the fact that certain nitrogen oxide species (e.g. nitroglycerin) have been used to treat vascular ailments such as angina for over 100 years, the discovery of endogenous generation of nitric oxide (NO) and its role in the regulation of vascular function took many by surprise since it represented a unique and novel signaling paradigm in mammalian biology. Since this discovery, there has been a virtual explosion of res Read More

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 incre Read More

This review includes the non-patent literature up to October 2004 that deals with selective neuronal nitric oxide synthase inhibitors (highest potency is for the neuronal isozyme). Some non-selective inhibitors or selective inducible nitric oxide synthase inhibitors are mentioned if they are related to compounds that are discussed; structures of these compounds generally are not given. In vitro inhibition constants are given either as I Read More

Diazeniumdiolate ions are convenient and, for a variety of applications, uniquely advantageous nitric oxide (NO) dosage forms. Ionic diazeniumdiolates generate bioactive NO in physiological fluids truly spontaneously (i. e., without metabolism or redox activation), with reliable half-lives ranging from 2 seconds to 20 hours depending on the ion's structure. They are generally simple-to-prepare solids with excellent sh Read More

The photochemistry and use of recently developed photosensitive precursors to nitric oxide (NO) are reviewed. As "caged NO" donors these precursors are able to deliver NO in a spatially and temporally controllable manner. These properties have made such precursors useful in applications in biology and medicine, especially in elucidating neurophysiological roles of NO and in new cancer therapies.

Recent comparisons of the pharmacological effects of nitric oxide (NO) and nitroxyl (HNO) donors have demonstrated that the responses to these redox-related nitrogen oxides are nearly universally dissimilar. These analyses have suggested the existence of mutually exclusive signaling pathways as a result of discrete chemical interactions of HNO and NO with a variety of critical biomolecules. Although the mechanisms o Read More

Hydroxyurea has emerged as a new therapy for sickle cell disease but a complete mechanistic description of its beneficial actions does not exist. Patients taking hydroxyurea show evidence for the in vivo conversion of hydroxyurea to nitric oxide (NO), which also has drawn interest as a sickle cell disease treatment. While the chemical oxidation of hydroxyurea produces NO or NO-related products, NO formation from the reacti Read More

FK409 was discovered during a screening program for prostaglandin like compounds from microbial products by measuring inhibition of platelet aggregation and vasodilation. FK409, a semisynthetic compound derived from acidic nitrosation of microbial broth, was shown to be a potent vasodilator with a similar pharmacological profile to organic nitrates such as nitroglycerin (NTG). FK409 dilated the larger diameter coro Read More

Because of the chemical and physical properties of nitric oxide, its effective use and delivery for therapeutic application represents a significant challenge. Accordingly, current understanding of nitric oxide biology largely stems from the use of nitric oxide prodrugs and adducts whose biological activities are based on their ability to release nitric oxide or a redox-related species. Among the structurally diverse ensemble Read More

Organic nitrates, such as nitroglycerin, have been used in clinical practice for more than one century for the treatment of angina, even before the identification of Nitric Oxide (NO) as the so-called Endothelium Derived Relaxing Factor (EDRF). Recently, multiple functions of this molecule in biology and pathophysiology have been discovered and alterations in the NO signalling pathway have often been associated with diseas Read More

Nitric oxide (NO) has been implicated in a wide variety of disease states. Both inhibitors and substrates of nitric oxide synthase (NOS) could have great therapeutic potential in the treatment of these diseases. There is considerable pharmacological interest in developing inhibitors of NOS, and hundreds of inhibitors have been identified. In contrast, the study on NOS substrates is less active. The advances in the identification, de Read More