The importance of the discovery of NO biology was recognized by award of the Nobel Prize in 1998. In the first decade after the identification of NO as endothelium-derived relaxing factor and the expanding roles of NO in biology, medicinal chemists focused upon developing inhibitors of the NOS isoforms, because of the proposed contributions of NO to cellular cytotoxicity and tissue damage, most notably from inducible NOS (iNOS) in inflammation, neuronal NOS (nNOS) in CNS excitotoxicity, and the toxicity of peroxynitrite . Somewhat ironically the new nitrate drugs being developed in parallel were described as NO donors and NO-enhanced medicines with cytoprotective properties . Classical nitrates continue to be of clinical use for angina pectoris, despite the clinical tolerance that is well documented for GTN, and controversy surrounding the phenomenon . The clinical efficacy of GTN is enhanced by its selective venodilator effect resulting in decreased cardiac preload and myocardial oxygen consumption. The classical nitrate, ISDN, in a cocktail with hydralazine entered clinical use in 2005 for cardioprotection in African-American males with heart failure, marking a move to chronic drug treatment with nitrates .
Hybrid nitrates that conjugate a nitrate group to a commonly used drug via a labile linker have been the subject of numerous preclinical and clinical studies. The companies pioneering the use of hydrid nitrates have in recent years allied with "big pharma" in the areas of nitrate anti-inflammatories, antihypertensives, and glaucoma therapeutics. The medicinal chemistry of a variety of hybrid nitrates has recently been reviewed , for example: HCT 3012 is a naproxen hybrid in Phase III clinical trials for pain and inflammation; NCX 4016 in various Phase II clinical studies is the most well-studied aspirin hybrid (NO-ASA); NCX 701, an acetaminophen hybrid is in Phase II trials for pain; and, NCX 1015 is a prednisolone hybrid in Phase I trials for inflammation (Fig. 1).
Sinitrodil, nicorandil, and nipradilol represent neo-classical nitrates, containing functionalities other than simple hydrocarbon or sugar skeletons, which influence biological activity, but which remain directed at vascular targets (Fig. 1). Nicorandil is a nitrovasodilator, also active at Katp channels, that is in preclinical and clinical studies for vascular diseases, including myocardial infarction [15,16]. Sinitrodil is a cardiovascular agent proposed to surpass classical nitrates because of reduced dilation of the smaller coronary and resistance vessels and the resultant effects on mean arterial blood pressure and heart rate [17,18]. Nipradilol, containing a pharmacophore with adrenergic antagonist activity, and used clinically as an anti-glaucoma therapeutic, was developed to exploit ocular nitrovasodilator activity, but subsequently has been shown to have neuroprotective actions [19-21].
Applications of nitrates beyond vascular targets are less common, but, supported by animal model data demonstrating cognition enhancement and neuroprotection, GT 1061 has recently entered clinical trials for Alzheimer's disease (AD) [22-24]; and, other exciting applications of nitrates as neuroprotective agents have also been described [25-27]. GT 1061 is an NO chimera, a nitrate that contains an ancillary pharmacophore designed to supplement the beneficial effects of nitrates in a specific disease state, in this case, neurodegeneration associated with AD [26,28]. In many brain regions, elevation of tissue cGMP levels and NO/cGMP signal transduction are triggered by activation of both the N-methyl-D-aspartate subtype of excitatory amino acid receptors (NMDAR) and cholinergic muscarinic receptor subtypes [29-31]. The NO/sGC/cGMP signal transduction system is important for modulating synaptic transmission and plasticity in brain regions such as the hippocampus and cerebral cortex, which are critical for learning and memory, and which are targeted in AD pathology [32-35]. Thus, GT 1061 was originally targeted at AD because NO plays a critical role in signal transduction cascades that are compromised in AD. Damage to cholinergic neurons has long been associated with AD, but recent evidence directly linking loss of NO/cGMP signalling, with NMDAR dysfunction, and the amyloid cascade theory of AD progression, unequivocally supports a need for supplementation of NO/cGMP in the AD brain [36,37]. GT 1061 has been studied in a variety of experimental paradigms where cognition deficits are induced, including: (a) injection of the muscarinic receptor antagonist scopolamine ; (b) administration of the cholinergic neurotoxin 192 IgG-saporin [39,40]; and (c) chronic, daily, bilateral, intracerebroventricular infusion of ^-amyloid peptide (A|31-40) . GT 1061 reversed cognition deficits in behavioral models including the Morris water maze, the step-through passive avoidance test, contextual memory, and a visual memory delayed matching to sample test.
There is general acceptance of the use of nitrates in indications with a vascular pathology; the field with which classical nitrates are closely associated. A more conservative attitude towards use of novel nitrates in other indications, such as neurological, may be explained by a number of factors. First, nitrates do not fit the contemporary, rational drug design paradigm: nitrates are extensively metabolized and bioactivated, and are expected to have multimeric actions and pleiotropic effects (though in most disease states this should be seen as a benefit rather than disadvantage). Second, there is a perception that cytotoxicity is inherently linked with NO, which partly derives from the study of NO as an atmospheric pollutant, before its renaissance as an essential component of life and health. The extensive drug discovery directed at inhibition of NOS can make the pursuit of nitrate drugs, that are generally almost universally described as NO donors, appear counterintuitive. Numerous reports on NOS
inhibitors showing cytoprotective and chemopreventive effects are counterpoised by a large body of data showing cytoprotection and chemoprevention by nitrates and NO donors.
Several pathophysiological conditions clearly involve disruption of cellular NO homeostasis, which argues for therapeutic benefit in modulation of NO, rather than simply inhibition of its formation or action. Nitrates are NO mimetics, but poor NO donors, which is probably relevant to the safety of nitrate therapeutics: there is no evidence for quantitative bioactiva-tion to NO; and at pharmacological concentrations the fluxes of NO detected are much lower than for genuine NO donors, such as the diazeniumdiolates (NONOates). There are numerous reports of the capacity, at higher concentrations in vitro, of NO and nitrosating agents (such as acidified NO-) to cause DNA-modification . The NO donor, diethylamine-NONOate, gaseous NO, and sodium nitrite are reported to be mutagenic in several bacterial strains in the reverse mutation assay (AMES test) [43,44]. The situation with nitrates is mixed: ISDN and several other nitrates have had negative AMES tests reported, whereas GTN was positive. There is no evidence for carcinogenicity of GTN or other clinical nitrates and several new nitrates have entered the clinic without genotoxicity concerns.
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