Rheumatoid arthritis, treatment inhibitors

A small-molecule inhibitor of tumor necrosis factor a, a protein involved in inflammatory diseases such as rheumatoid arthritis, has been identified <2005SCI1022>. Direct inhibition by the commercial biological agents Enbrel and Remicade has produced major advances in rheumatoid arthritis treatment and validated extracellular inhibition of this proinflammatory cytokine as an effective therapy. The new inhibitor 35 is composed of trifluoromethylphenyl indole and dimethylchromone moieties linked by a dimethylethylenediamine spacer. 

Cohen S, Fleischmann R (2010) Kinase inhibitors a new approach to rheumatoid arthritis treatment. Current Opin Rheumatol 22(3) 330-335... 

Adalimumab is a TNF-a inhibitor initially approved for the treatment of rheumatoid arthritis in 2003. It is approved for treatment of psoriatic arthritis and off-label uses and clinical... 

Arylmethyl-9-hydroxypyrazino[l,2-f]pyrimidine-l,8-dione derivatives have been claimed as anti-HIV agents <2005W02005/016927, 2005W02005/087766> 6,8-dioxo-pyrazino[l,2-f]pyrimidine-3-carboxamides 164 (Y = NH) <2004W02004/014354> and their saturated analogues <2004USP2004/034009> have been claimed as matrix metalloproteinase MMP-13 enzyme inhibitors, useful in the treatment of rheumatoid arthritis. 

Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone. 

Celecoxib has been approved for the treatment of osteoarthritis and rheumatoid arthritis, and rofecoxib has been approved for the treatment of osteoarthritis, acute pain and primary dysmenorrhea. Celecoxib and rofecoxib do not appear to differ in efficacy for the treatment of osteoarthritis. However, neither drug has efficacy greater than that of the non-selective NSAIDs. Since the COX-2 enzyme appears to play an important role in colon cancer the COX-2 inhibitors may find future uses in the treatment or prevention of colorectal cancer. 

Meloxicam (Mobic), recently introduced for the treatment of osteoarthritis, is also used for rheumatoid arthritis and certain acute conditions. Although meloxicam is sometimes reported to be a selective COX-2 inhibitor, it is considerably less selective than celecoxib or rofecoxib. Its adverse effects are similar to those of piroxicam and other NSAIDs however, the frequency of GI side effects is lower for meloxicam than for piroxicam and several other NSAIDs. 

The most recent treatment paradigm calls for earher, more aggressive treatment of rheumatoid arthritis. DMARDs are frequently employed along with NSAIDs in the initial treatment of the disease. The COX-2 inhibitors are often used because they are less likely to cause serious GI toxicity than are the nonspecihc COX inhibitors. The usual DMARD of choice for patients with mild rheumatoid arthritis is hydroxychloroquine or sulfasalazine methotrexate is used for those with moderate to serious disease. Other DMARDs are used if these agents are poorly tolerated or do not produce suf-hcient response. Combination therapy of methotrexate and another agent is also used to treat disease that is not responsive to individual DMARDs. 

The biosynthesis of the IL-12 cytokine is dependent upon various enzymes, including phosphodiesterase 4 (PDE4). Thus, PDE4 enzyme inhibitors act as functional IL-12 antagonists, and may have clinical application in the treatment of rheumatoid arthritis. 

Teng GG, Turkiewicz AM, Moreland LW Abatacept A costimulatory inhibitor for treatment of rheumatoid arthritis. Expert Opin Biol Ther 2005 5 1245. [PMID 16120053]... 

The two COX-2 selective inhibitors, celecoxib (1) and rofecoxib (2), marketed in 1999 and 2000, respectively, have quickly become blockbuster drugs (with annual sales of more than one billion dollars) for the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA). Many backups and competition drugs are sure to follow. Excitingly, some COX-2 selective inhibitors have been shown to inhibit cancer growth as well. ... 

Clinical use Rofecoxib (Sorbera et al., 1998) is a second generation COX-2 selective inhibitor. It was the second COX-2 selective drug to reach the market in 1999. Rofecoxib is used for the treatment of rheumatoid arthritis, osteoarthritis and pain. 

Tosyliminothiochromone-2-carboxylates 585 are inhibitors of interleukin-1 and are thus useful for the treatment of rheumatoid arthritis, multiple sclerosis, diabetes mellitus, atherosclerosis and septic shock <1995WO9514670>, and thiochromones possessing a sulfamoyloxy side chain at either C-6 or C-7 behave as steroid sulfatase inhibitors < 1999W O9952890>. 

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