Current Medicinal Chemistry - Volume 12, Issue 25, 2005

To the medicinal chemist uninitiated in the field, inflammation can be an intimidating research area to tackle. There is a bewildering array of prospective targets for antiinflammatory drugs, with countless enzyme inhibitors, receptor antagonists, and other experimental antiinflammatory agents already known. Despite many decades of research, the biology that underpins inflammation, the immune response to infection and injury, and the mechanistic basis for therapies, is still in need of considerable unravelling. Fortunately, the genomic/proteomic revolution that has been taking place is providing new tools and an unprecedented volume of new information that promises to dramatically improve our understanding of inflammatory networks, and how best to intervene in them for maximum therapeutic gain. In this issue, Hume et al. present a short commentary on inflammation and inflammatory targets of relevance to other articles that follow. They describe some factors that limit either the effectiveness of inflammatory targets or the rate of discovery of antiinflammatory drugs, and comment briefly on future prospects for targeting proteins that mediate inflammatory responses. Whitehouse completes the introduction by overviewing the historical development of antiinflammatory therapies, focussing on some of the problems encountered in drug development during the past century and some important lessons that were learned along the way. Brown describes antibody treatments for inflammatory arthritis (e.g. rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis), including some of their limitations as well as opportunities for developing new antibody based anti-inflammatory therapies. Kanwar also overviews antibody therapies, but for the treatment of multiple sclerosis, including properties of antibodies in animal models of experimental autoimmune encephalomyelitis (EAE). Numerous proteolytic enzymes are implicated in the pathogenesis of chronic inflammatory diseases. Abbenante and Le describe the current status of development of small nonpeptidic inhibitors of two such enzymes, the metalloprotease TACE (Tumour necrosis factor Alpha Converting Enzyme) and the cysteine protease Caspase-1 (formerly ICE, Interleukin Converting Enzyme). Such enzymes are responsible for producing the crucial proinflammatory mediators TNFα and IL1β, and selective inhibitors of such enzymes are expected to be effective antinflammatory drugs that should also be much cheaper and more accessible to the public than currently used antibody based therapies. Lee and Dominguez describe some clinical results for inhibitors of the serine/threonine kinase known as mitogen-activated protein kinase p38 (MAP kinase p38) and especially focus on inhibitor interactions with the best studied isoform, p38α protein. Kostadinova et al. overview peroxisome proliferator-activated receptors (PPARs) and their inhibitors in inflammation and disease. Reid surveys structures of inhibitors of secreted phospholipase A2 (group IIa) and discusses their potential roles as antiinflammatory drugs. Blakeney et al. survey some 30 GPCRs implicated in inflammation and describe structures and properties of some 60 agonists/antagonists with antiinflammatory activity. This issue represents only a tiny fraction of the already known number of inflammatory drug targets but offers a reasonable platform for benchmarking future developments in antiinflammatory drugs both for these targets and others.

This commentary is an introduction to a special issue on "Latest Developments in the Treatment of Inflammation". It outlines some key events in the inflammatory response to infection or injury and describes some of the important drug targets of relevance to the succeeding articles, which survey inhibitors of these targets as prospective or current antiinflammatory drugs. It also highlights important limitations in the validation of inflammatory drug targets, and in the rate of discovery and development of new antiinflammatory drugs.

Drugs to treat inflammation are discussed under the following headings: (1) random discoveries covering copper, salicylates, heterocyclic diones, ACTH, adrenal steroids and disease-modifying agents (DMARDs); these include Au(I)-thiolates, chloroquine, and hydroxychloroquine, minocycline, cyclosporin, salazopyrine, D-penicillamine and methotrexate; (2) programmed NSAID developments covering salicylates and fenamates, arylalkanoates, diones, non-acidic NSAIDs, clozic, lobenzarit and coxibs; (3) synthetic glucocorticosteroids; and (4) 'Biologicals' for neutralising pro-inflammatory cytokines. Clinical problems are highlighted, particularly unacceptable side-effects affecting the GI tract, skin, liver, etc. that caused many drugs to be withdrawn. Drug combinations may overcome some of these problems. The bibliography has selected reviews and monographs covering 50 years of publications.

Inflammatory arthropathies such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis are extremely common in the community, with a prevalence of up to 5%, and they cause substantial morbidity. The development of anti-TNF agents for use initially in rheumatoid arthritis, and subsequently more broadly in inflammatory arthritis, represents the biggest advance in management of these conditions since the introduction of corticosteroid agents, and is a major vindication of public funded arthritis research. However, there are limitations of even these highly effective agents. A significant minority of patients with inflammatory arthritis do not respond to these anti-TNF agents, they are associated with substantial risk of toxicity, require parenteral administration, and are extremely expensive. New antibody treatments in development can be divided into anti-cytokine agents, cell-targeted therapies, co-stimulation inhibitors, and treatments aimed at preventing joint erosion consequent on inflammation. This review discusses the state of the art in the development of these agents for management of this common group of diseases.

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas with demyelination. Disease is believed to be an autoimmune disorder mediated by activated immune cells such as T- and B-lymphocytes and macrophages/microglia. Lymphocytes are primed in the peripheral tissues by antigens, and clonally expanded cells infiltrate the CNS. They produce large amounts of inflammatory cytokines, nitric oxide (NO) that lead to demyelination and axonal degeneration. Although several studies have shown that oligodendrocytes (OLGs), the myelin-forming glial cells in the CNS, are sensitive to cell death stimuli, such as cytotoxic cytokines, anti-myelin antibodies, NO, and oxidative stress, in vitro, the mechanisms underlying injury to the OLGs in MS/EAE remain unclear. The central role of glutamate receptors in mediating excitotoxic neuronal death in stroke, epilepsy, trauma and MS has been well established. Glutamate is the major excitatory amino acid transmitter within the CNS and it's signaling is mediated by a number of postsynaptic ionotropic and metabotropic receptors. Inflammation can be blocked with anti-cell adhesion molecules MAb, simultaneously protected oligodendrocytes and neurons against glutamatemediated damage with the AMPA/kainate antagonist NBQX, and the NMDA receptor antagonist GPE, could thus be effective therapies for multiple sclerosis

TNF-α neutralising agents such as Infliximab (Remicade®), Etanercept (Enbrel®) and the IL-1 receptor antagonist Anakinra (Kineret®), are currently used clinically for the treatment of many inflammatory diseases such as Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis and psoriasis. These protein preparations are expensive to manufacture and administer, need to be injected and can cause allergic reactions. An alternative approach to lowering the levels of TNF-α and IL- 1β in inflammatory disease, is to inhibit the enzymes that generate these cytokines using cheaper small molecules. This paper is a broad overview of the progress that has been achieved so far, with respect to small molecule inhibitor design and pharmacological studies (in animals and humans), for the metalloprotease Tumour Necrosis Factor-α Converting Enzyme (TACE) and the cysteine protease Caspase-1 (Interleukin-1β Converting Enzyme, ICE). Inhibitors of these two enzymes are currently considered to be good therapeutic targets that have the potential to provide relatively inexpensive and orally bioavailable anti-inflammatory agents in the future.

Mitogen-activated protein kinase p38 is a serine/threonine kinase originally isolated from lipopolysaccharide (LPS) stimulated monocytes. There are four isoforms p38α, p38β, p38γ, and p38δ. The most thoroughly studied isoform is p38α, whose activation has been observed in many hematopoietic and nonhematopoietic cell types upon appropriate stimuli. Subsequently, p38α kinase has been shown to be involved in the biosynthesis of TNFα and IL-1β at the translational and transcriptional level. MAP kinase p38agr; represents a point of convergence for multiple signaling processes that are activated in inflammation and thus a key potential target for the modulation of cytokine production. The discovery and publication of p38α and the pyridinyl-imidazole inhibitor initiated a huge effort by many companies to develop p38α inhibitors as potential treatment for inflammatory diseases. Herein we provide a brief overview of recent reported clinical results for AMG 548, BIRB 796, VX 702, SCIO 469, and SCIO 323. However, our focus will be on the binding modes of these inhibitors and other p38 inhibitors in the recent literature.

The three isotypes of peroxisome proliferator-activated receptors (PPARs), PPARa, β/δ and γ, are ligand-inducible transcription factors that belong to the nuclear hormone receptor family. PPARs are implicated in the control of inflammatory responses and in energy homeostasis and thus, can be defined as metabolic and anti-inflammatory transcription factors. They exert their anti-inflammatory effects by inhibiting the induction of pro-inflammatory cytokines, adhesion molecules and extracellular matrix proteins or by stimulating the production of anti-inflammatory molecules. Furthermore, PPARs modulate the proliferation, differentiation and survival of immune cells including macrophages, B cells and T cells. This review discusses the molecular mechanisms by which PPARs and their ligands modulate the inflammatory response. In addition, it presents recent developments implicating PPAR specific ligands in potential treatments of inflammationrelated diseases, such as atherosclerosis, inflammatory bowel diseases, Parkinson's and Alzheimer's diseases.

Phospholipases A2 cleave membrane phospholipids to release arachidonic acid, the precursor to a large family of pro-inflammatory eicosanoids including prostaglandins and leukotrienes that have been proven to exacerbate numerous diseases that have an inflammatory component. Current therapies include NSAIDs' that inhibit cyclooxygenases (COX-1, COX-2) but have no effect on the production of leukotrienes or platelet activating factor (PAF). Inhibitors of PLA2 therefore offer the potential to block production of a more complete set of inflammatory substances through blockade at the onset of the cascade of reactions that follow arachidonic acid release. Many potent, bioavailable and selective inhibitors of human sPLA2 group IIA have been available for more than a decade and have provided compelling support for a causative role of sPLA2 group IIA in numerous studies involving animal models of inflammatory diseases. However, the true value of sPLA2 inhibitors for the treatment of human diseases has had to await phase II clinical trials which have only been completed in the last two years. This review presents the structurally diverse array of available sPLA2 group IIA inhibitors, their associated biological activity in animal models, and evaluation of therapeutic potential in phase II clinical trials in humans.

The focus of this review is on G protein-coupled receptors (GPCRs) for which nonpeptidic ligands are known and have been evaluated for the treatment of inflammatory conditions. GPCRs are the most prevalent class of cell surface proteins in pharmaceutical research today, and GPCR-targeting drugs account for one tenth of worldwide pharmaceutical sales. Of over 800 human GPCRs identified to date, several hundred are activated by peptides/proteins and just over 30 of these have been identified so far as potential therapeutic targets for the treatment of inflammatory diseases. This review highlights those GPCRs and over 60 structurally diverse nonpeptidic compounds that interact with them and display pro- or anti- inflammatory properties. Among these GPCR targets are the receptors for peptides like bradykinin, chemokines, complement anaphylatoxins, corticotropin releasing factor, endothelins, melanocortins, tachykinins, urocortins, as well as the protease activated receptors (PARs). Other peptide activated GPCRs implicated in inflammation, like those that bind angiotensin II, N-formyl peptides, galanin, neuropeptide Y, opioids and oxytocin, are only briefly discussed because there is either less direct association with inflammation or few/no nonpeptidic antiinflammatory ligands known. While it is still very early in the development of antiinflammatory drugs that target GPCRs, there is already a wealth of information supporting their important roles as cellular sentries in inflammatory diseases. New opportunities are emerging to evaluate antiinflammatory activities of potent and selective GPCR-binding ligands, including those being developed for other disease indications. In summary, GPCRs deserve a great deal more attention as potential therapeutic targets in inflammatory diseases.