Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 5, Issue 1, 2006

While it is often repeated that one cannot teach an old dog new tricks, it is likely that one can learn new tricks even from an old dog; and the same is certainly true for old drugs, as abundantly illustrated by the review articles in this special issue of Current Medicinal Chemistry. Even though most of them deal with very timely issues of cellular and molecular mechanism in the context of inflammation, much of the information discussed has been obtained with the help of pharmacological tools that are in some cases more than a century old, like aspirin [1], or which have been in constant use and study for as long as five decades, like the glucocorticoids [2]. In other examples, the field of investigation, rather than the specific pharmacological tool, is time-honored: the study of snake venoms in pharmacology has led to the seminal discovery of bradykinin and the development of a whole class of anti-hypertensive agents, dating back to the studies of brazilian pharmacologist Mauricio Rocha e Silva and his collaborators in the 1940's [3]. The more recent discovery of disintegrins and the development of novel analogues of snake venom disintegrins which have an impact on inflammation, in addition to effects on hemostasis, are among the most striking examples of the enormous potential of venoms as sources of powerful biological probes [4]. Another timehonored field is that of nitric oxide (NO) biology, which largely antedates the identification of NO itself as a central effector in biological processes as different as the control of vascular tone, inhibition of platelet aggregation, killing of intracellular microorganisms by macrophages and wound healing [5-8]: sodium nitroprusside, the effects of which are mediated by NO, was characterized as an anti-hypertensive agent in 1929 and became a standard treatment for acute control of severe hypertension in the 1950's [9] The articles gathered in this special issue follow either one or the other of these patterns. They either concentrate on old drugs that have unexpected effects when tested in novel systems, or they explore novel aspects of mediators that have been intensively studied over a long time, such as NO and snake venoms. Sometimes, they do both. It is clear that important, novel information continues to be generated through both approaches. This suggests that important advances in medicinal chemistry can be made by combining the properties of well-characterized agents available today. The reviews by Riley and colleagues [10] and Gaspar-Elsas and Elsas [11] in this issue provide an example of the first pattern. They review the effects of a number of well-known agents on granulocytes from opposite standpoints: while Riley and colleagues concentrate on the mature granulocytes of the neutrophil and eosinophil lineage, found in peripheral blood and inflammatory sites, Gaspar-Elsas and Elsas analyse the development of eosinophils in bone-marrow and other sites from hemopoietic progenitors and precursors. Even though their reviews address the two extremes of a leukocyte's life cycle, they are closely related by their emphasis in the ubiquitous process of apoptosis. From their contributions, it is clear that apoptosis plays a major role in the regulation of granulocyte numbers, by influencing both production and consumption. The mass of work they summarize also sheds novel life on the actions of inflammatory mediators and anti-inflammatory drugs, which are shown to influence granulocyte survival by acting at key steps in the control of apoptosis. However, such effects are also seen to depend strongly on the developmental stage of the cell being studied, so that certain agents, such as glucocorticoids, may affect apoptosis in strikingly different ways, depending on whether one looks at a mature or an immature cell. This adds a biological dimension to a field in which the response to a drug or mediator is often assumed to be solely determined by the presence of the ligand, its receptor and the corresponding signalling/effector elements. On the other hand, the articles by Shaw et al. [12], Assreuy et al. [13] and Ferreira et al. [14] exemplify the second pattern: they are linked by their common effort to highlight novel aspects of NO, which is as physiologically versatile as it is structurally simple. According to Shaw et al., adequate manipulation of NO in atherosclerotic lesions may provide a muchneeded means of controlling the progression of life-threatening atherosclerotic plaques. This view is linked to the increasing................

A subset of leukocytes, known as the granulocytes, are the body's first line of innate immune defense. The granulocytes are comprised of neutrophils, eosinophils and basophils of which the former two will be the focus of this review. Neutrophils defend the body against bacterial and fungal infection whilst eosinophils are thought to defend against parasitic invasions. Granulocytes are recruited to the site of infection or tissue damage where their relatively short half-life can be extended by regulatory external factors including hypoxic environments or agents that activate signaling pathways, such as NF-kB which is implicated in the up-regulation of anti-apoptotic genes. Granulocytes release various proteins, proteolytic enzymes and toxic oxygen products into the phagolysosome or surrounding environment destroying the invading organism. However, in order for inflammation to be resolved it is essential that granulocytes die by apoptosis and are phagocytosed by macrophages in a non-inflammatory fashion. This prevents the release of the cell's histotoxic contents into the extracellular milieu thereby reducing the potential for tissue damage. In instances when granulocytes fail to appropriately enter apoptosis or a defect in phagocytic clearance occurs the inflammatory response can be perpetuated, potentially resulting in the development and promotion of inflammatory disorders such as asthma or rheumatoid arthritis. Thus, selective enhancement of apoptosis and augmentation of macrophage clearance could allow targeting of inflammatory resolution to provide potential novel therapeutic agents for the treatment of inflammatory disorders.

The effects of a variety of widely used anti-inflammatory agents (dexamethasone, indomethacin, and montelukast) as well as ubiquitous mediators of inflammation (prostaglandin E2 and nitric oxide) on the development of murine eosinophils ex vivo and in vivo have been studied over the last decade. The results indicate that developing eosinophils differ markedly in their responses to these agents from the mature forms of the same lineage, studied either in allergic human subjects or experimental animal models of allergic disease. Most strikingly, glucocorticoids strongly enhance eosinophil development, both in vitro and in vivo. The enhancing effects are also observed during stress reactions and are strictly dependent on stress-induced glucocorticoid hormone production from the adrenal glands. Some, but not all, of the developmental effects of glucocorticoids on eosinophils could be accounted for their ability to prevent generation of nitric oxide through inducible NO synthase, which leads to apoptosis through the CD95-CD95L pathway. A novel mechanism for the effects of indomethacin in upregulating the development of eosinophils has also been documented. Evidence that lineage-specific as well as stage-specific cellular response programmes determine these different outcomes is discussed, along with the perspectives for future research.

Atherosclerosis, and its associated complications, are a major cause of morbidity and mortality, and it is now recognised as a chronic inflammatory disorder. Progression of inflammation depends on the balance between recruitment of inflammatory cells and their subsequent removal from a site of inflammation. Apoptosis, or programmed cell death, is a fundamental process governing cell survival and is a major determinant of the resolution of the inflammatory response. Apoptotic cells are instantly recognised for non-inflammatory clearance by phagocytes (e.g. macrophages) and removed from the vicinity of inflammation without the release of their pro-inflammatory cell contents. Nitric oxide (NO) plays an important role in many biological processes and has several anti-atherogenic properties including vasodilatation, inhibition of platelet activation and aggregation, and the regulation of apoptosis in a variety of cell types involved in atherogenesis. A critical early event during atherogenesis is injury to the endothelium. The ensuing damage results in endothelial dysfunction, including a reduction in the capacity of the endothelium to generate NO. Decreased NO bioavailability is likely to influence many cellular processes occurring within atherosclerotic lesions, including apoptosis. Modulation of apoptosis is a novel target for therapeutic intervention in the treatment of chronic inflammatory disorders, such as atherosclerosis. This modulation may help limit or resolve inflammation without the concomitant recruitment of subsequent inflammatory cells, thereby reducing the potential for further tissue damage. NO is a possible candidate for manipulation of atherosclerotic processes due to both its powerful anti-atherogenic characteristics and ability to affect apoptosis. This review highlights the role of apoptosis in atherosclerosis and discusses the therapeutic potential of NO to limit and/or resolve vascular inflammation.

Sepsis and septic shock continue to be a major cause of morbidity and mortality in critically ill patients. During the onset of sepsis, a massive inflammatory reaction is mediated via cell-derived cytokines and chemokines that target end-organ receptors in response to injury or infection. Polymorphonuclear leucocytes are critical effector cells during the inflammatory process and their migration to the infectious focus is extremely important for the local control of bacterial growth and consequently for the prevention of bacterial dissemination. In addition to the inflammatory process, sepsis and septic shock cause a profound loss in the peripheral vasomotor tone resulting in a huge decrease in the peripheral resistance, a central event in the derangement of hemodynamic and perfusional parameters. Nitric oxide (NO) is a simple molecule produced by numerous cell types that has been implicated in a wide range of physiological and pathological processes, exerting both detrimental and beneficial effects. It is an important modulator of neutrophil adherence and activation, of cardiovascular homeostasis and end organ perfusion. The induction of the inducible isoform of NO synthase leads to an increased NO production which is involved both in the impairment of neutrophil migration and in the cardiovascular disfunction present in sepsis and septic shock. Thus, a better knowledge of the role of NO in the inflammatory, cardiovascular and immune aspects of sepsis may provide us with more efficient therapeutic alternatives to treat sepsis and septic shock.

Recruitment of eosinophils into tissues is a feature of a variety of allergic diseases, including asthma and nasal allergy. Eosinophils secrete several preformed granule proteins (eosinophil peroxidase, major basic protein, eosinophil cationic protein and eosinophil-derived neurotoxin) and newly-generated substances (oxygen-derived toxic metabolites, lipid mediators, cytokines and chemokines), which may contribute to the exacerbation of the allergic diseases. In the past decade, NO has been recognized as a major immunomodulatory mediator of inflammatory responses, particularly in the lung, where it is believed to play a pivotal role in modulating pulmonary eosinophilia and airways hyperresponsiveness in both allergic animals and humans, as evidenced by functional, biochemical and immunohistochemical studies. The NOcGMP signaling cascade was initially implicated in the modulation of eosinophil functions; however, additional studies have demonstrated that direct cGMP-independent mechanisms may also play important roles in eosinophil functions. Much progress in understanding the influence of NO on eosinophil functions has been achieved with the use of selective and non-selective NOS inhibitors, as well as NO-donor compounds, along with NOS isoform gene knock-out mice. However, these studies have resulted in numerous controversies and conflicting findings, possibly as a consequence of the diversity of experimental models used, animal species employed, methods of immunization and challenge with allergens, amongst others. The present review summarizes the role of NO in modulating, in vivo and in vitro, eosinophil adhesion, chemotaxis, airways hyperresponsiveness and apoptosis, outlining the conflicting findings in the literature, with emphasis on the allergic inflammatory responses.

In response to a chemotactic gradient of inflammatory mediators and chemokines, neutrophils adhere to vascular endothelium and directly migrate, leaving blood vessels, toward inflamed tissue areas, to exert their primary defense function. These events are mediated by distinct classes of cell surface receptors in human neutrophils, that not only drive cell adhesion and motility, but also interfere with the cell's activation status, modulating different functions and survival. In this review we summarize the current understanding of the series of events that begins at the level of G-protein coupled receptor activation by chemoattractants, and the signaling pathways triggered by cell adhesion molecule interactions that lead to neutrophil adhesion, migration and activation during inflammation. Integrins, as adhesion receptors able to act as anchoring molecules (allowing firm cellular attachment to the ECM) and signaling receptors (transducing signals in both directions, outside-in and inside-out) are targets that potentially provide both therapeutic and diagnostic opportunities. We also present data obtained with integrin-selective ligands, the disintegrins, which could be useful tools to understand cellular processes as adhesion, migration, proliferation, activation and cell survival and may be also suggested as prototypes for designing therapeutic agents for the prevention or activation of integrin-mediated effects.

Novel discoveries in medicine have provided understanding of the mechanisms involved in the development and maintenance of pathologies, thereby leading to the identification of new therapeutic targets and consequently new drugs. Thalidomide, independently of its teratogenic effects, is one drug able to regulate the immune system. Deeper studies about thalidomide have started on the 90's, when some of its action mechanisms were elucidated. Following the initial description of high systemic TNF-α production in patients with erythema nodosum leprosum (ENL), and the reduction of TNF-α caused by the administration of thalidomide in these patients, the drug was shown to present multiple effects, making it difficult to understand the mechanism of its successful use in some pathologies. Such studies have extended the rational application of thalidomide to various disorders in which the participation of one or more factors modulated by the drug has been related. In this review, we describe some of the mechanisms of action of thalidomide, its collateral effects, and some of its pharmacodynamical properties. We also discuss the applications of the drug in various diseases, and especially in leprosy and multiple myeloma, on the basis of an extensive review of the literature.

Thalidomide ([2-(2,6-dioxo-hexahydro-3-(R,S)-pyridinyl)-1,3-isoindolinedione]), well known by its teratogenic effect, caused birth defects in up to 12,000 children in the 1960s. More recently, this drug was approved by the US Food and Drug Administration for the treatment of erythema nodosum leprosum, under restricted-use program, and a variety of new possible therapeutic applications have been described. This article will accomplish a review of medicinal chemistry aspects of thalidomide and state of the art in the development of new anti-inflammatory and immunomodulator drug candidates designed using thalidomide as lead-compound.