Current Pharmaceutical Design - Volume 8, Issue 3, 2002

Endothelial dysfunction defined as the impaired ability of vascular endothelium to stimulate vasodilation plays a key role in the development of atherosclerosis and in various pathological conditions which predispose to atherosclerosis, such as hypercholesterolemia, hypertension, type 2 diabetes, hyperhomocyst (e) inemia and chronic renal failure. The major cause of the endothelial dysfunction is decreased bioavailability of nitric oxide (NO), a potent biological vasodi-lator produced in vascular endothelium from L-arginine by the endothelial NO synthase (eNOS). In vascular diseases, the bioavailability of NO can be impaired by various mechanisms, including decreased NO production by eNOS, and / or enhanced NO breakdown due to increased oxidative stress. The deactivation of eNOS is often associated with elevated plasma levels of its endogenous inhibitor, NG NG-dimethyl-L-arginine (ADMA). In hypercholesterolemia, a systemic deficit of NO may also increase the levels of low density lipoproteins (LDL) by modulating its synthesis and metabolism by the liver, as suggested by recent in vivo and in vitro studies using organic NO donors. Therapeutic strategies aiming to reduce the risk of vascular diseases by increasing bioavailability of NO continue to be developed. Cholesterol-lowering drugs, statins, have been shown to improve endothelial function in patients with hypercholesterolemia and atherosclerosis. Promising results were also obtained in some, but not all, vascular diseases after treatment with antioxidant vitamins (C and E) and after administration of eNOS substrate, L-arginine, or its cofactor, tetrahydrobiopterin (BH4). Novel strategies, which may produce beneficial changes in the vascular endothelium, include the use of natural extracts from plant foods rich in phytochemicals.

Biological role of nitric oxide (NO), functioning of isoforms of NO synthetases (NOS) and pharmacology of principle NO-donors were reviewed. NO donating characteristics and pharmacology of 23 mesoionic oxatriazoles (MOTA) were compared with those of 5-morpholinosydnonimine (SIN-1), S-nitroso-N-acetylpenicillamine (SNAP), sodium nitroprusside (NaNP) and glyceryl trinitrate (GTN). It is concluded that in vitro NO donating profile of MOTA hardly can be used as a predicting measure for their pharmacological activities either in vitro or in vivo. If anything, fast NO releasers seem to be stronger vasorelaxants than MOTA with slow NO releasing properties. Still, among representatives of this last category of MOTA one may find efficient antithrombotic and thrombolytic agents. For instance, MOTA 5-oxides were more potent thrombolytics than SIN-1, SNAP or NaNP. Also MOTA with potent anti-platelet action in vitro seem to be potent relaxants of tracheal strips. In summary, by manipulating the chemical structures of MOTA one may obtain relative selectivity towards vasorelaxant, anti-platelet, thrombolytic or tracheorelaxant properties. Thus different categories of MOTA might be designed with a hope of achieving hypotensive, antithrombotic, thrombolytic or anti-asthmatic drugs.

Nitric oxide (NO), a molecular messenger synthesized by nitric oxide synthase (NOS) from L-arginine and molecular oxygen, is involved in a number of physiological and pathological processes in mammalians. Three structurally distinct isoforms of NOS have been identified: neuronal (nNOS), endothelial (eNOS) and inducible (iNOS). Although NO mediates several physiological functions, overproduction of NO by nNOS has been reported in a number of clinical disorders including acute (stroke) and chronic (schizophrenia, Alzheimer's, Parkinson's and AIDS dementia) neurodegenerative diseases, convulsions and pain overproduction of NO by iNOS has been implicated in various pathological processes including septic shock, tissue damage following inflammation and rheumatoid arthritis. On the contrary, NO produced by eNOS has only physiological roles such as maintaining physiological vascular tone. Accordingly, selective inhibition of nNOS or iNOS vs eNOS may provide a novel therapeutic approach to various diseases in addition selective inhibitors may represent useful tools for investigating other biological functions of NO. For these reasons, after the identification of N-methyl-L-arginine (L-NMA) as the first inhibitor of NO biosynthesis, design of selective NOS inhibitors has received much attention.In this article the recent developments of new molecules endowed with inhibitory properties against the various isoforms of NOS are reviewed. Major focus is placed on structure-activity-selectivity relationships especially concerning compounds belonging to the non-aminoacid-based inhibitors.

Nitric oxide (NO) deficiency has been implicated in many pathological and physiological processes within the mammalian body providing a plausible biologic basis for the use of NO replacement therapy in these conditions. Exogenous NO sources may hopefully constitute a powerful way to supplement NO when the body cannot generate enough for normal biological functions.This theory has opened up the possibility of designing new drugs that are capable of delivering NO into tissues and the bloodstream in a sustained and controlled manner. This objective has been reached by grafting an organic nitrate structure onto existing molecules with various spacers such as aliphatic or aromatic chain, with different degree of complexity.This approach has led to the synthesis of several new chemical entities in various pharmacological classes, whose profile seems to challenge the parent drug not only on the basis of new pharmacological properties but also on a better toxicological and safety profile.In this article, general aspects on NO and NO donors are reviewed. Major focus is placed upon recent developments of novel NO donors, NO releasing device(s) as well as innovative improvements to conventional NO donors. Several examples are given in some important therapeutic indications such as cardiovascular diseases (NO-aspirin), pain and inflammation (NO-paracetamol), osteoporosis and urinary incontinence (NO flurbiprofen with aliphatic spacer), Alzheimer's disease (NO-flurbiprofen with anti-oxidant spacer), respiratory disorders (NO-steroids).

Nitric oxide (NO), produced from L-arginine by the activity of constitutive and inducible NO synthases, has been implicated in a wide range of physiological and pathophysiological processes. Low concentrations of this mediator play homeostatic roles, whereas NO is up-regulated in a number of pathological states and can have damaging effects. Pharmacological modulation of NO levels or NO biosynthesis may be a therapeutic strategy for a number of conditions, although the reported results can be some times controversial. Inhibitors of NO synthases exhibit different selectivity for the neuronal, endothelial or inducible isoforms, which contributes to their beneficial and detrimental effects. Recent developments in this field may offer an alternative for the treatment of inflammatory disorders, pain, neurological diseases, shock, atherosclerosis or cancer.

Research in the nitric oxide (NO) field has enormously extended in the past 20 years and maintaining an overview of NO research has become very difficult. NO biology has been extensively studied and several aspects of its role in physiology and pathology have been clarified. The final outcome of these researches is that NO is a double edge sword mediator in that it can exert beneficial or detrimental effect depending on the physiopathological context. However, the development of drugs based on these new knowledge has been strongly impaired by these double face of NO. The purpose of this review is to briefly outline the role of this almost ubiquitous mediator and give a state of the art on the development of new drugs based on the NO concept rather than summarising the large number of NO donors that have been synthesised since there are several specific review dealing with this matter. The final picture that comes out by our analysis is that it goes without any doubt that much has still to be done to develop new drugs. Thus, the development of new drugs still represents a challenging task.There has been an enormous interest on nitric oxide (NO) since its discovery and its involvement in many physiological and pathological events has been demonstrated or postulated. Drugs which acts through NO such as the organic nitrates have been used in therapy since many years and it would have been predicted that due to the enormous effort profuse in understanding the biology of NO, new drugs based on all these new findings would have been ready developed. So far this matter has resulted in a challenging task since, as it is summarised below, NO has multiple action that are linked to both beneficial and pathological effect. Thus, in some cases we want to prevent NO production while in other cases we want deliver or increase NO production. This review will briefly addresses some of the major areas of biology where NO has been involved and give an overview of what is the state of the art in developing drugs that works through NO.