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Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) (v.10, #2)
Editorial [Hot-Topic: Molecular Mechanisms in Rheumatic Diseases:Rationale for Novel Drug Development (Guest Editor: Charles J. Malemud)] by Charles J. Malemud (pp. 72-72).
Novel therapies for the treatment of rheumatoid arthritis (RA) appear to be on the horizon. Any advances in thedevelopment of novel therapeutics for RA will only be made possible as a result of our improved understanding of howimmune-mediated inflammation contributes to the pathogenesis and progression of the RA disease process. Thus, recentadvances in unraveling the way in which ‘cross-talk’ between intracellular signaling pathways contributes to RA pathologyhave resulted in the recognition that only through the suppression of multiple signal transduction pathways can amelioration ofdisease activity occur in human RA. In that regard, several intracellular protein kinase small molecule inhibitors are now beingevaluated in human RA clinical trials. In addition, development of novel computational strategies combined with the use ofproteomic databases have now been employed to enhance the rationale design of small molecule inhibitors that have thepotential to be added to the armamentarium of already existing RA therapies. Finally, this research has also resulted in animproved design of small molecules which have the capacity to interfere with pro-inflammatory cytokine-induced geneexpression to dampen the RA inflammatory response.
Molecular Mechanisms in Rheumatic Diseases: Rationale for Novel Drug Development - Introduction by Charles J. Malemud (pp. 73-77).
Novel therapies for treating rheumatoid arthritis (RA) will largely be developed as a consequence of ourimproved 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 recentdevelopments in how new drugs will be designed for the therapy of RA by employing proteomic databases and other wellvalidatedcomputational strategies. Furthermore, recent advances in the recognition that pro-inflammatory cytokines andthe interferon family of proteins activate intracellular signal transduction pathways which control immune-mediatedinflammatory responses as well as the way in which newly identified regulators of inflammation such as the Toll-likereceptors contribute to RA are also discussed.
Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways by Charles J. Malemud (pp. 78-84).
A skewed repertoire of pro-inflammatory cytokines produced by the Th1 subset, one of the hallmarks of rheumatoidarthritis (RA), is characterized by an overabundance of pro-inflammatory cytokines. Tumor necrosis factor-.., 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-.. are primarily responsiblefor immune-mediated inflammation of RA by activating Janus kinases (JAK) -1, -2, -3, p38 kinase, C-Jun-Nterminalkinase, extracellular signal-regulated kinase 1/2 and the phosphatidylinosotide-3-kinase/Akt/mTor pathways. Activationof these signaling pathways results in up-regulation of pro-inflammatory cytokines, cyclooxygenase-2, matrixmetalloproteinases, pro-angiogenesis proteins and anti-apoptosis proteins, the latter resulting in abnormal survival of activatedT- and B-cells. Further, IL-17 also regulates the differentiation of CD4+ T-helper cells by inducing a Th17 T-cellsubset, 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 signalingabnormalities. The results of in vitro and studies in animal models of arthritis have indicated that inhibiting individual signalingpathways 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 exhibitingacceptable safety and tolerability profiles have only marginal and transient clinical effectiveness. These resultssuggested that future RA clinical studies using these or other kinase inhibitors will have to consider strategies designed tosimultaneously inhibit multiple kinase pathways.
Computational Strategies for the Development of Novel Small Molecule Rheumatoid Arthritis Therapies by Tarek M. Mahfouz, David H. Kinder (pp. 85-91).
Rheumatoid arthritis is a chronic autoimmune disorder that causes joint disfigurement and destruction leadingto reduced quality of life. Effective drug therapies include the Disease Modifying Anti-Rheumatic Drugs which can helpimpede the progression of the disease but are not always effective. It is, therefore important to identify novel and effectivetherapies to combat this debilitating disorder. Several bioinformatics tools and computational approaches can be utilizedto identify novel and effective therapies for rheumatoid arthritis and these are presented here.
Current and Future Therapeutic Targets of Rheumatoid Arthritis by Yuan Ming Di, Zhi-Wei Zhou, Chun Guang Li (pp. 92-120).
Rheumatoid arthritis (RA) is a chronic systematic autoimmune disease which affects about 1% of the populationworld wide. This article aimed to identify current therapeutic targets for RA based on data from the literature anddrug 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 forRA 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 andwere analysed using the PANTHER Classification System. According to the PANTHER analysis, most commonly involvedpathways 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 vascularendothelial growth factor (VEGF) receptor signalling pathway. Accordingly, current clinical agents for the treatmentof RA mainly include corticosteroids, non-steriodal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumaticdrugs (DMARDs). In addition, a number of investigational targets for RA have been identified and many noveldrugs for RA therapy are under investigation. Current approaches to handle RA aim to ameliorate inflammation, to relievepain, and most importantly to protect the cartilage, joints and bones from further damage by blocking proinflammatorymolecules and inhibit the production of matrix-degrading factors. New drugs for RA with improved efficacy and safetyshould be developed.
Immunological Targets in Inflammation from the Small Molecule Perspective by Angelica M. Bello, Meena K. Purohit, Tracy Jun Yang Cui, Slater Brandon Stead, Lakshmi P. Kotra (pp. 121-131).
Inflammation and autoimmune disorders have received much greater attention in the recent years due to theelucidation of various molecular mechanisms and the discoveries of various cytokines and other proteins involved in theseprocesses. 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 severaladvantages over protein therapeutics including their affordability for chronic treatments. In this review article, recentsuccesses targeting various inflammatory cytokines and the corresponding receptors such as TLRs, interleukins, p38.. aswell as recent strategies for developing small molecule antagonists using rational models are discussed.
Anti-Inflammatory Activity of Tetracyclines: Applications to Human Disease by P. J. Higgins, M. Draper, M. Nelson (pp. 132-152).
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 hasalso been demonstrated in both animal models and clinical studies. This review describes the experimental evidencewhich demonstrates the various non-antibacterial anti-inflammatory activities of tetracyclines and discusses possiblemechanisms of action of these drugs.