The p38 Mitogen-Activated Protein (MAP) kinase, a serine/threonine kinase, is one of the best characterized kinases in the inflammatory process. Among the four identified p38 isoforms (p38α, p38β, p38γ, and p38δ), the α-form is the most fully studied and plays a central role in the biosynthesis of the proinflammatory cytokines i.e. IL-1β and TNF-α at the translational and transcriptional levels. Antagonism of these proinflammatory cytokines has been recognized as an effective possibility for the development of new drug candidates. The characterization of the pharmacological profile displayed by the selective p38 inhibitor prototype SB203580, proved its disease-modifying activity in the adjuvantinduced arthritis model. This strongly suggests that adequate modulation of production of these cytokines can bring significant benefits to the therapy of chronic inflammatory diseases. In addition to its important role for the secretion of proinflammatory cytokines, p38 is also involved in the activation of matrix metalloproteinases and the induction of COX- 2 transcription, proteins that are involved in the process of tissue destruction and inflammation. Because of its multiple functions in modulating the inflammatory response, it is expected that p38 inhibiting drugs will treat the underlying cause of chronic inflammatory diseases and stop their progression. The archetypal small molecule p38 inhibitors are the pyridinylimidazoles and these structures formed the basis for much of the early research. More recently a number of nonimidazole based p38 inhibitors such as the ureas, pyrazoles, pyrazoloheteroaryls, pyridazines, indoles, amides, pyridines, triazolopyridines, etc containing a variety of functionality have been reported to inhibit cytokine activity. This article provides a critical account of these different heterocycles reported for p38 MAPK inhibition and covers the recent research in the development of anti inflammatory agents.
p38α mitogen activated protein kinase (MAPK) inhibitors provide a novel approach for the treatment of inflammatory disorders. A series of fifteen pyrazolyl urea derivatives (3a—o) were synthesized and evaluated for their p38α MAPK inhibition and antioxidant potential. Compounds 3a—e, 3g and 3h showed low micromolar range potency (IC50 values ranging from 0.037 ± 1.56 to 0.069 ± 0.07 µmol/L) compared to the standard inhibitor SB 203580 (IC50 = 0.043 ± 3.62 µmol/L) when evaluated for p38α MAPK inhibition by an immunosorbent-based assay. Antioxidant activity was measured by a 2,2′-diphenyl-1-picryl hydrazyl radical (DPPH) free radical scavenging method and one of the compounds, 3c, showed better percentage antioxidant activity (75.06%) compared to butylated hydroxy anisole (71.53%) at 1 mmol/L concentration. Compounds 3a—e, 3g and 3h showed promising in vivo anti-inflammatory activity (ranging from 62.25% to 80.93%) in comparison to diclofenac sodium (81.62%). The ulcerogenic liability and lipid peroxidation activity of these compounds were observed to be less in comparison to diclofenac sodium. These compounds also potently inhibited the lipopolysaccharide (LPS)-induced TNF-α release in mice (ID50 of 3a—c = 19.98, 11.32 and 9.67 mg/kg, respectively). Among the screened compounds, derivative 3c was found to be the most potent and its binding mode within the p38α MAPK is also reported.
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