Tyrosine kinases inflammatory diseases

Bruton s tyrosine kinase inhibitors Approaches to potent and selective inhibition, preclinical and clinical evaluation for inflammatory diseases and B cell mahgnancies 12JMC4539. 

Receptor tyrosine kinases (RTKs) have been implicated as therapeutic targets for the treatment of human diseases including cancers, inflammatory diseases. A series of Pyrrolo [3,2-c] pyridine-4-one 2-indolinone derivatives as tyrosine kinase inhibitors were designed and synthesized. They were found to inhibit the tyrosine kinase activity associated with vascular endothelial growth factor receptor 2(VEGF-R2). Their biological evaluation results and structure-activity relationship will be discussed. 

As it was mentioned in the previous sections, the active principle of Fostamatinib disodium (88) is Tamatinib (92), which is formed by enzymatic hydrolysis of 88 in the intestine. As in the case of lymphoma, the effect of 88 in autoimmune diseases is related to inhibition of Spleen tyrosine kinase (Syk) by 92 [241, 242]. As Syk has the central role in transmission of activating signals within B cells, inhibition of this enzyme lowers expression of a number of pro-inflammatory cytokines and hence leads to immunosuppression [243], Fostamatinib has shown significant efficacy in the treatment of patients with rheumatoid arthritis not responding to Methotrexate (272) (a drug which is used conventionally in therapy), although a number of adverse events were observed [244], If these results are confirmed once Phase III studies are completed, it may hnd a place in the treatment of patients with rheumatoid arthritis with poor response to conventional therapy (Fig. 11). 

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