Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry - Volume 5, Issue 4, 2006

Inflammatory reactions have attracted wide interest lately, as a consequence of their contribution to abnormalities additional to the long-established immune system-related diseases. The advancements in molecular biology and genomic/post-genomic sciences point to a comprehensive synthesis of information on the physiology and the pharmacological interventions of “inflammation-related” conditions. Without excluding the decisive character of inflammatory mediators, such as histamine and cytokines, and the latest significant developments in atopy/allergy, autoimmunity and infections, recent evidence provides insights into the participation of related mechanisms in a variety of other common human conditions, including cardiovascular and endocrine diseases, neurological disorders, and cancer; thus expanding the endeavours of immunopharmacological investigation. Interestingly, inflammation and the implicated cells and mediators, nowadays are regarded as “double-edged swords”; a characterization derived from their remarkable duality in favoring immune system function as well as in eliciting inflammatory and pro-inflammatory responses [1-4]. The multi-system modulatory pathways implicated in the polarization of T helper (TH) lymphocytes of the TH1 and TH2 type [5], which are basically considered as regulators of immunostasis in health and disease [6]; and the organ and tissue specific, sometimes unexplained and paradoxical responses of prostaglandins [2] may serve as mere paradigms of the dual character of related endogenous circuits. The basis for these phenomena is not understood adequately, thereby urging the need to identify the homeostatic and self-regulating feedback mechanisms. In this concept, the efficacy, toxicity and drug interactions in therapeutic regiments, involving old and new agents [2, 5], need thorough evaluation, aiming at optimally exploiting the latest data for the development of beneficial end-points. Regarding pharmacological intervention in the endogenous cross-talk, prototype drugs, already under phase II clinical trials, have been directed towards a specific molecular target; yet simultaneously modulating multiple signaling cascades in highly conserved homeostatic pathways, like the cellular stress response [7-10] The articles in this special issue seek (i) to summarize the state-of-the-art in newly recognized mediators of homeostatic mechanisms of the organism; (ii) to explore novel aspects of well established inflammatory cells and mediators; and (iii) by classical and genomic pharmacological studies, to evaluate some current and anticipated anti-inflammatory strategies. These fundamental approaches integrate immunopharmacological data, challenging efficient therapeutic intervention. Commencing with glucocorticoids, the prominent example of drugs developed on an endogenous anti-inflammatory pathway, the article by Prof. Perretti's group [11] elaborates on the most recent research on specific effectors of antiinflammation, like peptides, polyunsaturated fatty acid derivatives and the anti-inflammatory short-lived gases nitric oxide (NO) and carbon monoxide (CO). In order to control inflammatory pathologies, the authors propose that understanding of a given anti-inflammatory circuit would be of great help in developing more efficient drugs that mimic the way our own body assures the inflammatory response. However, long established inflammatory mediators, like histamine, have not been ignored by immunopharmacologists. The discovery of the novel histamine H4 receptor has lead to a reassessment of the role of histamine in several pathophysiological conditions and offered to the amine a new perspective beyond its traditional H1- mediated immunopharmacological properties [12]. Thus, as described by Dr Venable and Dr Thurmond in this issue [12], the H4 receptor could be a good medicinal chemistry target for the rational development of compounds to treat a variety of allergic and inflammatory conditions. Likewise, our group presents recent data on the differentially released pro-inflammatory and antiinflammatory mediators from the somewhat neglected mast cell, that support additional versatile effector roles for these phenotypically diverse components of the immune system, beyond their historical involvement in type I hypersensitivity reactions [13]. Consequently, Prof. Mannaioni's group provides a comprehensive risk-benefit insight not only into the widely prescribed non-steroidal anti-inflammatory drugs (NSAIDs, aspirin; Coxibs like celecoxib, rofecoxib) and acetaminophen, but also into the newly developed NO-NSAIDs or COX-inhibiting NO donors (CINODs) and CO-releasing molecules (CO-RMs) [14].....

Understanding the way our body switches off host defence responses has yielded some of the most innovative recent discoveries in inflammation research. In reality the concept is not new, and was already implicit in early publications of the 1970s' which showed that during inflammation, glucocorticoids are increased in the circulation and that these protect the host from over-shooting and ensuing self-inflicted injury. Stemming from the first example of drugs developed on an endogenous anti-inflammatory pathway, that of the glucocorticoid, we have here touched upon other counterregulatory breakpoints, such as those centred on melanocortins; the annexin 1 system; the polyunsaturated fatty acid derivatives lipoxins and resolvins; galectin-1 and selected others, including novel chemical entities engineered to release anti-inflammatory gases and factors originally discovered in the developmental field. We propose that understanding the molecular mechanisms switched on by a given anti-inflammatory mediator and the events it modulates in target cells will be of great help in developing innovative ways to control inflammatory pathologies. This seems quite articulated and with a degree of complexity in the group of developmental axonal guidance factors. We propose that drugs discovered along this philosophy will have a better compliance and would be theoretically devoid of side effects since they will be acting by mimicking the way our own body assures the inflammatory response is restricted both spatially and temporally.

Histamine, which is known to play a role in most inflammatory conditions including allergy, asthma and autoimmune diseases, is a ubiquitous chemical messenger that has numerous functions. The inflammatory responses of histamine have long been believed to be mainly mediated by the histamine H1 receptor. Indeed the importance of histamine in the pathology of many diseases, like asthma, has been defined by whether traditional antihistamines, which are H1 receptor antagonists, are efficacious. The discovery of a fourth histamine receptor (H4) has prompted the questioning of these assumptions. The H4 receptor is expressed on mast cells, eosinophils, basophils, dendritic cells and T cells suggesting that it may play an important role in inflammatory responses. The discovery of selective ligands for this receptor has been crucial in uncovering its function. These tools have been used to show that the receptor plays a role in mast cell and eosinophil chemotaxis, as well as cytokine production in dendritic cells and T cells. In addition H4 receptor antagonists have efficacy in a variety of inflammatory animal models including peritonitis, colitis and airway inflammation models. These data suggest that the H4 receptor is an attractive medicinal chemistry target for possible treatment of inflammation, allergy and asthma. Herein we describe the recent advances regarding the biology of the histamine H4 receptor, as well as detail the progress in developing imidazole and non-imidazole based modulators of this receptor as anti-inflammatory therapies.

Mast cells (MCs) were first described by Paul Ehrlich as well fed granular cells that stain metachromatically. Today MCs are regarded as multifunctional, granulated, tissue-dwelling cells distributed in the perivascular spaces and connective tissues of every major organ of the body. Their long recognized phenotypic diversity might be associated not only with their anatomic distribution and mediator repertoire, but also with their functional characteristics related to the regulation of effector pathways. In addition to their historical involvement in type I hypersensitivity response, MCs have emerged as versatile effector cells with functional diversity and homeostatic functions in non-IgE-mediated inflammatory responses, autoimmunity, bidirectional interactions with the neuroendocrine circuit, the urinary, gastrointestinal, cardiovascular and endocrine systems, in metabolism and malignancy. Thus, MCs appear to receive, integrate and transmit a wide range of signals in their microenvironment, coordinated by the differential release of their pro-inflammatory and anti-inflammatory granular mediators. Understanding the heterogeneity of this complex cellular communication may provide a tool for selective pharmacological intervention directed to specific MC subsets.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a structurally diverse group of similarly acting compounds that are widely prescribed and used for the management of pain associated with inflammatory conditions. Our present aim is to choose a leading drug for each class of NSAIDs, and to discuss the debated issues still pending about that drug, in order to weigh the risk/benefit ratio according to the current hypotheses on its mode of action. The leading compounds of the past and present which we have selected within this framework are aspirin, acetaminophen, celecoxib and rofecoxib. The discovery of nitric oxide (NO) in the last decade has resulted in proposing new NO-donors. Particularly interesting in this area has been the synthesis of NO-releasing anti-inflammatory drugs. The addition of NO to aspirin and to other NSAIDs has resulted in molecules that maintain their inhibitory effects on the cyclooxygenases (COX) but are devoid of cardiovascular, renal and gastrointestinal toxicity. The purpose of this review is also to update the “state-of-theart” of new classes of anti-inflammatory drugs such as COX-inhibiting nitric oxide donors (CINODs) and carbon monoxide (CO) releasing molecules (CO-RMs) as future tools in the therapy of inflammation and cellular proliferation.

Asthma is a common, chronic condition that is usually treated by the combination of inhaled steroids and β2 agonists on a when required basis. More recently, two further agents have been licensed for use: leukotriene receptor antagonists and very recently anti-IgE. This review describes a number of other possible treatment modalities. Some are well developed and already in Phase III clinical trials, others involve the use of drugs already on the market for other indications and a number are reasonably speculative.

Ocular allergies are one of the most common diseases presenting to the general ophthalmologist. Allergic eye disease includes a spectrum of different clinical entities: the seasonal and perennial allergic conjunctivitis and the more severe forms vernal keratoconjunctivitis and atopic keratoconjunctivitis. A wide spectrum of topical pharmacological agents has been developed for the treatment of the different forms of ocular allergy. These include mast cell stabilizers, pure antihistamines, new dual-acting agents with antihistamine and mast-cell stabilizer properties and non-steroidal antiinflammatory drugs (NSAIDs). All these drugs are very effective in controlling signs and symptoms of mild and moderate forms of allergic reaction and are mainly free of adverse reaction in the chronic use. Topical corticosteroids remain the mainstay in the aggressive treatment of sight-threatening forms of allergic conjunctivitis, although their long-term use is limited by the risk of severe ocular side effects. For this reason, newer immunosuppressive drugs, such as cyclosporine and tacrolimus, have been tested in the treatment of some forms of ocular allergy demonstrating an high safety profile. New potential therapeutic strategies include the modulation of the immune system through a switch of the allergic response from a Th2-dominated immune profile towards a Th1 response.

Ageing and inflammation might be considered as natural partners. Numerous mechanisms of an inflammatory basis for several age-associated diseases have been identified. Some markers of inflammation are already being integrated into clinical medicine. Furthermore, existent anti-inflammatory drugs and novel candidates have been found to specifically target inflammation pathways in the ageing processes. In this review, we focus on the current knowledge on the field, from the molecular and cellular level to the therapeutic potential of anti-inflammatory agents. First, we present several theories of ageing, in order to explore the involvement of inflammation and to define targets of intervention. Then, we discuss the current approaches and applications as well as the future trends in research regarding the involvement of antiinflammatory agents in the ageing processes.

Along with advances in the genome sequencing and microarray technologies, many attempts have been made to understand the human diseases systemically. Here, literatures regarding genomic studies on allergic diseases are reviewed, especially by focusing on microarray-based transcriptome studies. In earlier patient-oriented transcriptome studies related to allergy and inflammation, only a few projects seem to be successful considering the amounts of time, labor and research grants. Most frequently observed among the problems in such studies are contamination by a different cell type having a certain highly expressed transcript that may cause a virtual increase in the transcript number in the whole population even where the major cell type lacks it. The successful transcriptome studies are therefore commonly obtained by using cell lines, highly purified cells or gene-targeting cell lines for microarray analysis as the first screening. A cell-type specific transcriptome database is also useful for determining whether an increase of a certain transcript in inflammatory tissues reflects an increase in its expression level or an increase in the number of inflammatory cells. Nevertheless, high quality RNA samples are necessary for obtaining reproducible results in the present transcriptome assays using clinical samples. In this context, analysis for genome-wide chromatin structure will be useful to understand the transcriptome more precisely. Considering the rapid development of microarray and data mining technologies, it is well expected.

Pharmacogenomics, a fascinating, emerging area of biomedical research is strongly influenced by growing availability of genomic databases, high-through-put genomic technologies, bioinformatic tools and artificial computational modeling approaches. Multinational clusters, such as the regional and internet-driven pharmaco-grids generated an entirely new environment for research and development in pharmacology. Although the field of pharmacogenomics is in its infancy, the promise of pharmacogenomics lies in its potential to predict genomic sources of interindividual variability in drug response (both efficacy and toxicity), thus allowing individualization of therapy to maximize effectiveness and minimize risk. Thus, pharmacogenomics holds the promise for individualized medicine adapted to each person's own genetic makeup. Environmental factors including diet, age, and lifestyle as well as infection can influence a person's response to medicines, but understanding an individual's genetic background is thought to be the key to creating personalized drugs with greater efficacy and safety. Similar to other biomedical fields, in allergic and autoimmune diseases pharmacogenomics combines traditional pharmaceutical sciences such as biochemistry with annotated knowledge of genes, proteins, and single nucleotide polymorphisms (SNP). One of the major challenges now are developing and applying the statistical and computational capacity to store, manage, analyze and interpret the wealth of data being generated. This review summarizes the recent pharmacogenomic trends in inflammatory diseases with particular attention to autoimmune conditions and asthma.