Rheumatoid arthritis, treatment factor cytokine 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. 

Two remarkable successes of cytokine therapy are the treatment of multiple sclerosis with interferon-p and the treatment of rheumatoid arthritis and inflammatory bowel disease with tumor necrosis factor-a inhibitors. 

Tanacetum parthenium (Asteraceae), commonly known as feverfew, is a popular herbal remedy used a prophylactic in the treatment of migraine [88]. Studies have revealed that the action of feverfew is probably mediated by the sesquiterpene lactone parthenolide. Indeed, feverfew and parthenolide produce anti-inflammatory and antinociceptive effects in experimental animals [89]. Parthenolide is a potent inhibitor of the transcription factor NF-kB activation, a key regulator of pro-inflammatory protein production, such as cytokines, COX-2 and inducible nitric oxide synthase [90]. However, a clinical study revealed that feverfew did not provide any benefit in the treatment of rheumatoid arthritis [91]. Additional clinical studies must be carried out to explore the feverfew efficacy as an analgesic. 

NF-kB comprises a family of inducible transcription factors that serve as relevant mediators of the inflammatory response. This factor is also involved in protecting cells from undergoing apoptosis in response to DNA damage or treatment with cytokine [89]. Normally, NF-kB is kept inactive by a cytoplasmic inhibitor of kB (IkB) proteins, which are phosphorylated by a cellular kinase complex known as IKK, made up of two kinases, IKK-a and IKK-p. The phosphorylation of IkB by these kinases leads to the degradation of the proteins and to the translocation of NF-kB to the nucleus. Once in the nucleus, NF-kB activates gene expression of cells exposed to growth factors and cytokines [90,91]. Activation of the NF-kB pathway is thus involved in the pathogenesis of chronic inflammatory diseases such as rheumatoid arthritis and asthma... 

MAPKAP-K2 (MK-2), a direct substrate of p38 MAPKs, has been shown to play an important role in the production of pro-inflammatory cytokines, such as tumor necrosis factor-a (TNF-a), interleukin-1 a (IL-la) and IL-6. Thus inhibition of MK-2 kinase activity may potentially be useful for treatment of inflammatory diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease. Two classes of MK-2 inhibitors based on carboline or pyrazinoindolone templates are highlighted. Extensive SAR efforts lead to compounds with single-digit nanomolar molecular potency. Further optimization of pyrazinoindolone-based inhibitors provides compounds with the sub-micromolar cellular potency. 

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