Rapid Approaches To (-)-MK 801 Maleate A 205804 In Detail By Detail Detail

At present eight modest molecule kinase inhibitor drugs and a handful of protein/antibody therapeutics targeting kinases have been authorized for human use.

A large number of kinases from different signal transduction pathways have been the targets of interest for the treatment of inflammation and autoimmune disorders. One class of such kinases have been the A 205804 mitogen activated protein kinases, which has been summarized in a recent review, and hence will not be covered in this chapter. This review will cover the recent publications, primarily from 2006?2007, describing inhibitors of IKK2, Syk, Lck, and JAK3. Inhibitors of kinases such as BTK and Fyn are not covered in this review. Some of the publications cited in this review refer to the inhibitors reported earlier for that kinase. A large number of patents on kinase inhibitors describe, sometimes with very little, if any, information on the biological profile of compounds. This chapter will not cover such disclosures.

IKK2 phosphorylates the Ser32 and Ser36 residues of I?B bound to NF ?B. The phosphorylated complex is ubiquitinated by E3RS ligase and degraded by proteasome to generate the active NF ?B. The transcription factor then translocates to the nucleus A 205804 and induces the transcription of proinflammatory cytokines and matrix metalloproteases. Inhibition of IKK2 has been pursued as a potential therapy to treat disorders related to inflammation and autoimmunity. Based on the critical role of NF ?B in the immune system and on the data from knockout mice, it has been postulated that chronic inhibition of this transcription factor could lead to opportunistic infections and hepatic toxicity.

In LPSstimulated THP 1 cells, compound 1 inhibited TNF production with IC50_0. A 205804 34 uM, while BMS 345541 was less potent in this test with IC50_4 uM. Oral administration of compound 1 to mice inhibited the LPS induced TNF levels in the serum with ED50_10 mg/kg. A structurally related, imidazo thieno pyrazine derivative, 4, has been reported to inhibit IKK2 with IC50_13 nM and IKK1 with IC50_390 nM.