Abstract
Nitrates are an important class of drug for cardiovascular therapy under continuous development. Hybrid nitrates and NO chimeras, respectively, release a non-nitrate drug molecule or contain an ancillary pharmacophore; both approaches are designed to amplify or synergize the therapeutic activity of the nitrate in specific disease indications. Current drug discovery of new nitrate drug classes for indications beyond the vasculature emphasizes the need to better understand nitrate metabolism, bioactivation, and bioactivity. There is an opportunity to increase the selectivity of nitrates for target cells and tissues exploiting different bioactivation apparatus and mechanisms, beyond the serendipitous selectivity of many nitrates for bioactivation in hypoxic tissue. Structural modifications of nitrates can be envisioned that target specific enzymes for bioactivation, for example, those upregulated in cells under pathophysiological conditions. The biological half-life of GTN is in the order of minutes and several NO-NSAID nitrates cannot be detected intact in target tissue or even in plasma, yet contemporary nitrate drugs are often described as releasing NO in a sustained fashion for several hours. This apparent dilemma is resolved if one considers nitrates to provide a sustained source of "NO bioactivity," certainly of longer duration than that provided by true NO. The biological and clinical data suggest that there are multiple bioactivation pathways accessible to nitrates and multiple sites of action, and also that the mediators of bioactivity include but are not limited to NO itself.
Original language | English (US) |
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Title of host publication | Radicals for Life |
Subtitle of host publication | The Various Forms of Nitric Oxide |
Publisher | Elsevier |
Pages | 347-380 |
Number of pages | 34 |
ISBN (Print) | 9780444522368 |
DOIs | |
State | Published - 2007 |
Externally published | Yes |
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology