Rheumatoid arthritis kinases

KC706 stabilizes the inactive conformation of the mitogen-activated protein kinase p38a, a protein kinase involved in inflammatory reactions and cardiovascular functions. KC706 therefore holds the potential to treat conditions such as rheumatoid arthritis, psoriasis, inflammatory bowel disease and cardiovascular disease. This compound is currently being tested in phase II clinical trials with patients suffering from rheumatoid arthritis. 

Interleukin 1 (IL-1) is produced mainly by activated monocytes-macropha-ges, and its principal action is to stimulate thymocytes. A pleiotropic cytokine, IL-1 induces the expression of a large diversity of cytokines such as IL-6, leukaemia inhibitory factor (LIF), and other proinflammatory molecules (Di-marello 1994). IL-1 and TNF-a carry out as part of their function increasing the expression of NF-/cB and JNK (c-Jun N-terminal kinase). The importance of IL-1 in OCS is demonstrated because the IL-1-receptor-deficient mouse is resistant to ovariectomy (OVX)-induced bone loss (Lorenzo et al. 1998). The importance in pathological bone loss is also illustrated by the fact that treatment with IL-1 receptor antagonist slows down bone erosion for patients affected with rheumatoid arthritis (Kwan et al. 2004). IL-1 increases osteoclast differentiation rather than mature osteoclast activity, and infusion of IL-1 into mice induces hypercalcemia and bone resorption. Finally, IL-1 and TNF-a... 

C. Hydroquinone inhibits the enzyme tyrosine kinase, which converts tyrosine to melanin. It also damages melanocytes. Becaplermin (A) is a recombinant human platelet-derived growth factor that is useful in enhancing wound healing. Etanercept (B) is a recombinant fusion protein approved for treatment of psoriatic arthritis and rheumatoid arthritis. Botulinum toxin (D) is a purified form of bofu-linum foxin fype A approved for fherapy of blepharospasm and sfrabismus. 

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

In investigations by the author (1), Chen (2), and Cochran (3), imidazo-, (I), pyrido[2,3-d]pyrimidin-7-ones, (II), and isoquinoline derivatives, (HI), respectively, were prepared, which were effective in treating p38 kinase-mediated disorders by modulating IL-1, IL-6, and IL-8 and TNF-a. These agents were used in treating pathophysiological disorders such as rheumatoid arthritis, fever, and reduction of bone resorption. 

It is now recognized that protein kinases play an important role in intra-and intercellular communications. These enzymes are consequently directly involved in cell proliferation. The p38 kinase, for example, regulates the production of key inflammatory mediators. Excess expression of this factor is involved in the pathology of rheumatoid arthritis, psoriasis, and Crohn s disease. A rather complex protein kinase inhibitor, which... 

Hu Y, Green N, Gavrin LK, Janz K, Kaila N, Li HQ, Thomason JR, Cuozzo JW, Hall JP, Hsu S, et al. Inhibition of Tpl2 kinase and TNFalpha production with quinohne-3-carbonitriles for the treatment of rheumatoid arthritis. Bioorg. Med. Chem Lett. 2006 16 6067-6072. 

In myasthenia gravis synaptic transmission at the neuromuscular junction is impaired most cases have an autoimmune basis and some 85% of patients have a raised titre of autoantibodies to the muscle acetylcholine receptor. The condition is probably heterogeneous, however, as about 15% do not have receptor antibodies, or have antibodies to another neuromuscular junction protein (muscle specific kinase) and rarely it occurs with penicillamine used for rheumatoid arthritis. 

Coulthard LR, Taylor JC, Eyre S, Robinson JI, Wilson AG, Isaacs JD et al (2011) Genetic variants within the MAP kinase signalling network and anti-TNF treatment response in rheumatoid arthritis patients. Ann Rheum Dis 70 98-103... 

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