Ptive immune responses and suppress the production of synovial lymphokines zus Tzlich to block CCT239065 the production of metalloproteinases by synoviocytes. To r JNK evaluate in arthritis, the selective inhibitor SP600125 JNK was tested in the rat adjuvant model.11 13 The compound is a reversible inhibitor that Bl cke ATP wettbewerbsf HIGEN all three isoforms of JNK. The model of adjuvant arthritis by immunization with completely Ndigem Freund’s adjuvant and in s-dependent T cell-dependent Heavy polyartikul Rer destructive arthritis induced. The administration of SP600125 reduced paw swelling, but the effect was relatively modest. In contrast, animals treated with SP600125 a dramatic decrease in bone and cartilage L Emissions through R Ntgen analysis determined.
The effect was h Highest probably the suppression of effector mechanisms, such as the production of MMP synoviocytes, pleased t that. The AZD8330 initial immune response, because the drug was administered one week after the first immunization Analysis of the extracts common animals treated with SP600125 supports this conclusion, since the JNK inhibitor significantly reduced AP-1 and MMP-binding expression. In vitro kinase assays also showed that JNK activity t in the synovium was suppressed. Although SP600125 inhibits all three isoforms of JNK, it is possible to change that isoform selective inhibitor k Nnte the same benefit from a reduced risk of toxicity Have t. This problem was due to the evaluation of animal models of arthritis in JNK1 and JNK2 knockout M Directed nozzles.
Because JNK2 isoform is the gr Te of synoviocytes ge U Ert initial studies were in JNK22 / 2 animals with collagen arthritis.14 passive passive transfer model was carried out used because it is independent Ngig of T cells and Haupt chlich effector phase of arthritis. Although a modest level of protection was observed in joint JNK22 / 2 mouse, the benefit was much less than that in the adjuvant arthritis model, observed using a JNK inhibitor. JNK2 deficiency had. No effect on clinical arthritis or joint expression of AP-1 and MMP13 The protective effect of JNK1 deficiency in transgenic M Usen studied TNFa. JNK12 / 2 Mice were treated with human TNF transgenic M usen Backcrossed and clinical outcome was assessed. No difference in the synovial inflammation, bone erosion, cartilage damage or cellular Re infiltration of the synovial membrane were hTNFtg JNK12 / 2 compared to controls.
15 evaluation note JNK phosphorylation of JNK signaling showed decreased Mice JNK12 / 2 hTNFtg. However, phospho c levels were in the synovial membrane in June in both groups Similar. These data suggest that JNK2 may compensate for lack of JNK1 in this model. Therefore, a JNK inhibitor is likely to ben Term to both JNK1 and JNK2 target. An orally bioavailable JNK inhibitor AS601245 entered tested in the pr Clinical models.16 This connection Born in a dose-dependent-Dependent release of TNF-alpha in a mouse model of endotoxin shock. AS601245 was also effective in arthritis induced by collagen, reduces swelling and arthritis scores Foot Clinic. Histological analysis revealed reduced synovial inflammation and cartilage erosion. Unlike SP600125, this compound demonstrated optimized potent inflammatory and protective effect of the matrix.