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Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates

  • ID: 39363
  • October 2003
  • Lead Discovery
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The autoimmune diseases are receiving increasing attention in the pharmaceutical industry as progress is made in the understanding of immune and inflammatory processes. It is predicted that the annual value of the market for drugs used to treat autoimmune disease will exceed $20 billion in the next few years. Rheumatoid arthritis is one of the more common and difficult to treat autoimmune diseases and there is a great deal of interest in the discovery of novel drugs to treat this condition.

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Summary<BR><BR>Introduction<BR><BR>Rheumatoid Arthritis and its Treatment<BR><BR>Drugs in Development for the Treatment of Rheumatoid Arthritis<BR><BR>Drugs targeting the metabolism of arachidonic acid <BR>Cyclooxygenase (COX) Inhibitors <BR><BR>Table 1. Selective COX2 inhibitors <BR>Drugs targeting other sites of arachidonic acid metabolism <BR>Phospholipase A2 Inhibitors <BR>Lipoxygenase Inhibitors <BR>Variations on NSAIDs <BR><BR>Table 2. Drugs in development targeting arachidonate metabolism <BR>Drugs targeting inflammatory cytokines <BR>Biological Inhibitors of cytokines <BR>Anti-TNF Monoclonal Antibodies <BR>TNF receptors and binding proteins <BR><BR>Table 3. Biopharmaceutical approaches to neutralizing TNF <BR>Other TNF receptor family members <BR>RANK <BR>Osteoprotegerin <BR>Interleukin-1 antagonists <BR>Other cytokine-targeted biologicals <BR>Interleukin-6 <BR>Interleukin-8 <BR>Interleukin-10 <BR>Interleukin-12 <BR>Interleukin-15 <BR>Interleukin-18 <BR>Lymphotoxin &#946; <BR>B-lymphocyte stimulator <BR>Comment <BR><BR>Table 4. Biopharmaceutical Products targeting IL-1 and other cytokines <BR>New Chemical Entities (NCEs) designed to inhibit cytokines <BR>Inhibitors of p38 mitogen activated protein kinase (MAPK) <BR>Inhibitors of cytokine activating enzymes <BR>Inhibitors of Phosphodiesterase type 4 <BR>Other approaches to cytokine inhibiting NCEs <BR><BR>Table 5. New Chemical Entities (NCEs) targeting cytokine synthesis <BR>Drugs targeting the movement and activation of inflammatory leukocytes <BR>Inhibitors of chemotaxis <BR>Antagonists of the complement fraction 5a <BR>Chemokine Antagonists <BR><BR>Table 6. Drugs targeted at leukocyte chemotaxis <BR>Drugs targeting Adhesion Molecules <BR>Selectins <BR>Lymphocyte Function Antigen-1 (LFA-1, CD11a) antagonists <BR>Very Late Antigen-4 (VLA-4) antagonists <BR><BR>Table 7. Drugs targeting adhesion molecules <BR>Other Adhesion Molecule Targets <BR>Drugs designed to specifically regulate lymphocyte activation <BR>Inhibitors of lymphocyte intracellular enzymes <BR>Macrolide immunosuppressants <BR>Selective inhibitors of nucleotide metabolism <BR><BR>Table 8. Inhibitors of lymphocyte intracellular mechanisms <BR>Drugs targeting cell surface receptors on lymphocytes <BR>CD2 <BR>CD3 <BR>CD4 <BR>CD20 <BR>CD25 <BR>CD40 and CD40 Ligand <BR>CD80 (B7) <BR>CD152 (CTLA4) <BR><BR>Table 9. Biopharmaceuticals targeting lymphocyte cell surface molecules <BR>Vaccines and desensitizing agents <BR><BR>Table 10. Vaccines and Desensitizing agents <BR>Anti-proliferative Agents for Rheumatoid Arthritis <BR><BR>Table 11. New approaches to anti-proliferatives for rheumatoid arthritis <BR>Protease Inhibitors <BR>Matrix Metalloprotease Inhibitors <BR>Elastase Inhibitors <BR>Cathepsin Inhibitors <BR><BR>Table 12. Protease Inhibitors for Rheumatoid Arthritis <BR>Anti-angiogenic Agents for Rheumatoid Arthritis <BR><BR>Table 13. Anti-Angiogenic Agents <BR>Targets for novel anti-angiogenic molecules <BR>Growth Factors <BR>Cytokines <BR>Chemokines <BR>Matrix Metalloproteases <BR>Plasminogen activators <BR>Angiostatic molecules <BR>Cell adhesion molecules <BR>Analgesics for Rheumatoid Arthritis <BR><BR>Table 14. Analgesics for Arthritis <BR><BR><BR>

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The autoimmune diseases are receiving increasing attention in the pharmaceutical industry as progress is made in the understanding of immune and inflammatory processes. It is predicted that the annual value of the market for drugs used to treat autoimmune disease will exceed $20 billion in the next few years. Rheumatoid arthritis is one of the more common and difficult to treat autoimmune diseases and there is a great deal of interest in the discovery of novel drugs to treat this condition.<BR><BR>Rheumatoid arthritis is a chronic syndrome characterized by non-specific, usually symmetrical inflammation of the peripheral joints, manifested by the formation of hypertrophied synovia known as panni. Pannus formation mirrors the destruction of articular and peri-articular structures, with or without generalized manifestations. The condition differs from osteoarthritis not only through the obligatory involvement of the immune system but also because disease onset occurs early on in life, generally between the ages of 20 and 50, although it can begin at any age.<BR><BR>Since the birth of the modern pharmaceutical industry just over 100 years ago with the synthesis of aspirin, non-steroidal aspirin-like anti-inflammatory drugs (NSAIDs) have been the mainstay of the treatment of rheumatoid and other forms of arthritis. It is generally accepted that NSAIDs relieve the symptoms of arthritis such as pain and swelling without changing the course of underlying disease. There have been considerable efforts to develop drugs which modify disease progress and these have met with variable success. Immunosuppressants such as cyclosporine or anti-metabolite drugs such as methotrexate are effective but have dose-limiting adverse effects.<BR><BR>During the last few years however, basic research efforts have significantly progressed our understanding of autoimmune disorders such as rheumatoid arthritis. The disease is caused by increased chemotactic and immunostimulatory activity within the joints of sufferers resulting in an influx of inflammatory cell. The presence of activated immune cells increases local levels of cytokines and other inflammatory mediators propagating this process and supporting pannus proliferation and neovasculaturization, cartilage and bone erosion and eventual joint destruction.<BR><BR>Greater understanding of rheumatoid arthritis etiology has given rise to a large number of potential molecular targets for the development of improved therapeutic candidates. LeadDiscovery's state of the art report, "Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates" provides a comprehensive analysis of current and future molecular targets. Likewise the report evaluates new drug development activity categorizing emerging therapeutics according to their molecular targets.<BR><BR><BR>Although significant efforts have resulted in the development of the COX2 inhibitors celebrex and vioxx, one of the most exciting developments in the management of rheumatoid arthritis has been the introduction of the anti-TNF biopharmaceuticals remicade and enbrel. These drugs represent a real step forward in the development of anti-inflammatory therapies. There is now an increasing number of inflammatory cytokines which have become targets for therapeutic intervention with biologicals such as monoclonal antibodies or immuno-fusion proteins. There is also encouraging evidence that cytokines can be targeted by orally active medicinal chemicals. This report offers an analysis of cytokine targets and therapeutics on the market or in development.<BR><BR>The increasing knowledge of the immune system has revealed a number of targets for specific regulation of immune cells and in particular the process of antigen presentation, lymphocyte activation and leukocyte chemotaxis. The disease modifying arthritis drug arava selectively suppresses lymphocyte activation by inhibiting nucleotide synthesis and new drugs with similar mechanisms of action are in development. Methotrexate remains one of the most widely used disease modifying drugs in rheumatoid arthritis and attempts are being made to discover improved anti-proliferatives that are more specific and better tolerated. Biologicals which block lymphocyte cell surface receptors thereby preventing activation or adhesion, and molecules that limit chemotaxic are also showing encouraging therapeutic activity; each of these areas is addressed in this report. <BR><BR>Pannus proliferation is a primary feature of rheumatoid arthritis and therefore the development of anti-proliferative agents represents an opportunity for treating this disease. Another strategy for obtaining the same result is the development of anti-angiogenic agents to prevent the vascularization of inflamed joint tissues. There is considerable overlap in this area with drugs being developed to treat cancer and this report continues with an analysis of approaches that may increase synovial apoptosis or reduce proliferation or angiogenesis.<BR><BR>One of the cardinal manifestations of rheumatoid arthritis is joint destruction. This feature results from the infiltration of various inflammatory cells into the pannus and the progression of synoviocytes into a phenotype that supports matrix destruction. This process involves the release of various proteases and the inhibition of these enzymes represents a further strategy in the treatment of rheumatoid arthritis. The report therefore concludes with an analysis of matrix metaloproteinases, elastases and cathepsins; how these enzymes contribute to disease progression and how the drug development sector is targeting these enzymes.<BR><BR>This report therefore overviews each of the major components of rheumatoid arthritis including cytokine production, leukocyte chemotaxis and adhesion, lymphocyte activation, synovial proliferation, angiogenesis and matrix degradation. In this overview we consider almost 50 molecular targets and more than 150 products being developed by nearly 100 companies therefore representing not only a complete analysis of current areas of research activity but also a thorough examination of therapeutic candidates emerging from this activity. In short "Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates" represents a key tool to anyone wishing to select new drug discovery targets or to evaluate drug development activity relating to rheumatoid arthritis.<BR><BR>

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