Title:p38 MAP Kinase Inhibitors as Anti inflammatory Agents
Volume: 13
Issue: 14
Author(s): Mohammad Amir, K. Somakala and Sazid Ali
Affiliation:
Keywords:
Anti inflammatory, Imidazole, p38 inhibitors, Kinases, Urea, Pyrazolyl urea.
Abstract: 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 -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.
