Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry - Volume 10, Issue 2, 2011

Novel therapies for the treatment of rheumatoid arthritis (RA) appear to be on the horizon. Any advances in the development of novel therapeutics for RA will only be made possible as a result of our improved understanding of how immune-mediated inflammation contributes to the pathogenesis and progression of the RA disease process. Thus, recent advances in unraveling the way in which ‘cross-talk’ between intracellular signaling pathways contributes to RA pathology have resulted in the recognition that only through the suppression of multiple signal transduction pathways can amelioration of disease activity occur in human RA. In that regard, several intracellular protein kinase small molecule inhibitors are now being evaluated in human RA clinical trials. In addition, development of novel computational strategies combined with the use of proteomic databases have now been employed to enhance the rationale design of small molecule inhibitors that have the potential to be added to the armamentarium of already existing RA therapies. Finally, this research has also resulted in an improved design of small molecules which have the capacity to interfere with pro-inflammatory cytokine-induced gene expression to dampen the RA inflammatory response.

Novel therapies for treating rheumatoid arthritis (RA) will largely be developed as a consequence of our improved understanding of immune-mediated inflammatory responses that regulate the progression of the disease process. This Special Mini “Hot-Topic” Issue of Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, entitled, Molecular Mechanisms in Rheumatic Diseases: Rationale for Novel Drug Development explores several recent developments in how new drugs will be designed for the therapy of RA by employing proteomic databases and other wellvalidated computational strategies. Furthermore, recent advances in the recognition that pro-inflammatory cytokines and the interferon family of proteins activate intracellular signal transduction pathways which control immune-mediated inflammatory responses as well as the way in which newly identified regulators of inflammation such as the Toll-like receptors contribute to RA are also discussed.

A skewed repertoire of pro-inflammatory cytokines produced by the Th1 subset, one of the hallmarks of rheumatoid arthritis (RA), is characterized by an overabundance of pro-inflammatory cytokines. Tumor necrosis factor-α, interleukin- 1 (IL-1), IL-6, IL-7, IL-8, IL-21, IL-12/IL-23, IL-15, IL-17, IL-18, IL-32, and interferon-γ are primarily responsible for immune-mediated inflammation of RA by activating Janus kinases (JAK) -1, -2, -3, p38 kinase, C-Jun-Nterminal kinase, extracellular signal-regulated kinase 1/2 and the phosphatidylinosotide-3-kinase/Akt/mTor pathways. Activation of these signaling pathways results in up-regulation of pro-inflammatory cytokines, cyclooxygenase-2, matrix metalloproteinases, pro-angiogenesis proteins and anti-apoptosis proteins, the latter resulting in abnormal survival of activated T- and B-cells. Further, IL-17 also regulates the differentiation of CD4+ T-helper cells by inducing a Th17 T-cell subset, and a subpopulation of T-regulatory (Treg) cells. Although Treg cells are sufficiently abundant in RA synovial fluid, they fail to induce immune tolerance suggesting a functional deficiency likely coupled to putative protein kinase signaling abnormalities. The results of in vitro and studies in animal models of arthritis have indicated that inhibiting individual signaling pathways can blunt the synthesis of several of the pro-inflammatory biomarkers characteristic of human RA pathology. However, RA clinical trials indicated that small molecule inhibitors of JAK-1, -2-, 3 and/or p38 kinase while exhibiting acceptable safety and tolerability profiles have only marginal and transient clinical effectiveness. These results suggested that future RA clinical studies using these or other kinase inhibitors will have to consider strategies designed to simultaneously inhibit multiple kinase pathways.

Rheumatoid arthritis is a chronic autoimmune disorder that causes joint disfigurement and destruction leading to reduced quality of life. Effective drug therapies include the Disease Modifying Anti-Rheumatic Drugs which can help impede the progression of the disease but are not always effective. It is, therefore important to identify novel and effective therapies to combat this debilitating disorder. Several bioinformatics tools and computational approaches can be utilized to identify novel and effective therapies for rheumatoid arthritis and these are presented here.

Rheumatoid arthritis (RA) is a chronic systematic autoimmune disease which affects about 1% of the population world wide. This article aimed to identify current therapeutic targets for RA based on data from the literature and drug target related databases. Identified targets were further analysed using a powerful bioinformatics tool, PANTHER (Protein ANalysis THrough Evolutionary Relationships). Additionally, we explored future possible therapeutic targets for RA and discussed the possibility of discovering novel drugs with improved efficacy and reduced toxicity for RA treatment. Data on current clinical drugs for RA treatment were extracted from the US Food and Drugs Administration (FDA) website. Candidate targets of RA were extracted from three online databases: Drugbank, Therapeutic Target Database (TTD) and Potential Drug Target Database (PDTD). A total of 95 clinical protein targets for RA have been identified and were analysed using the PANTHER Classification System. According to the PANTHER analysis, most commonly involved pathways in current RA targeting includes inflammation mediated by chemokine and cytokine signalling pathways, angiogenesis, p53 pathway, de novo purine biosynthesis, T-cell activation, apoptosis signalling pathway and vascular endothelial growth factor (VEGF) receptor signalling pathway. Accordingly, current clinical agents for the treatment of RA mainly include corticosteroids, non-steriodal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). In addition, a number of investigational targets for RA have been identified and many novel drugs for RA therapy are under investigation. Current approaches to handle RA aim to ameliorate inflammation, to relieve pain, and most importantly to protect the cartilage, joints and bones from further damage by blocking proinflammatory molecules and inhibit the production of matrix-degrading factors. New drugs for RA with improved efficacy and safety should be developed.

Inflammation and autoimmune disorders have received much greater attention in the recent years due to the elucidation of various molecular mechanisms and the discoveries of various cytokines and other proteins involved in these processes. These discoveries are helping develop novel therapeutics including small molecules and protein therapeutics (biologics) for the treatment of sterile and nonsterile inflammatory disorders. Small molecule drugs have several advantages over protein therapeutics including their affordability for chronic treatments. In this review article, recent successes targeting various inflammatory cytokines and the corresponding receptors such as TLRs, interleukins, p38α as well as recent strategies for developing small molecule antagonists using rational models are discussed.

Tetracyclines possess anti-inflammatory characteristics which are largely independent of their antibacterial activity. A variety of in vitro biologic effects have been reported for tetracyclines in both immune and non-immune cells. The in vivo therapeutic efficacy of tetracyclines in diseases such as rheumatoid arthritis, multiple sclerosis, and stroke has also been demonstrated in both animal models and clinical studies. This review describes the experimental evidence which demonstrates the various non-antibacterial anti-inflammatory activities of tetracyclines and discusses possible mechanisms of action of these drugs.