Free Content MAP Kinase p38Inhibitors: Clinical Results and an Intimate Look at Their Interactions with p38α Protein

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Mitogen-activated protein kinase p38 is a serine/threonine kinase originally isolated from lipopolysaccharide (LPS) stimulated monocytes. There are four isoforms p38α, p38β, p38γ, and p38δ. The most thoroughly studied isoform is p38α, whose activation has been observed in many hematopoietic and nonhematopoietic cell types upon appropriate stimuli. Subsequently, p38α kinase has been shown to be involved in the biosynthesis of TNFα and IL-1β at the translational and transcriptional level. MAP kinase p38agr; represents a point of convergence for multiple signaling processes that are activated in inflammation and thus a key potential target for the modulation of cytokine production. The discovery and publication of p38α and the pyridinyl-imidazole inhibitor initiated a huge effort by many companies to develop p38α inhibitors as potential treatment for inflammatory diseases. Herein we provide a brief overview of recent reported clinical results for AMG 548, BIRB 796, VX 702, SCIO 469, and SCIO 323. However, our focus will be on the binding modes of these inhibitors and other p38 inhibitors in the recent literature.

Keywords: amg 548; birb 796; dgf in; dgf out; il-1β; map kinase; p38 inhibitors; scio 469; tnfα

Document Type: Review Article


Affiliations: Departments of Molecular Structure and Medicinal Chemistry , Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799, USA.

Publication date: December 1, 2005

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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