The mitogen-activated protein kinase (MAPK) p38 is a Ser/Thr kinase, originally 
isolated from lipopolysaccharide-stimulated monocytes. There are four isoforms 
of the enzyme (p38alpha, p38beta, p38gamma and p38delta), which differ in tissue 
distribution, regulation of kinase activation and subsequent phosphorylation of 
downstream substrates. These enzymes also differ in sensitivity to p38 MAPK 
inhibitors. The most thoroughly studied isoform is p38alpha, for which 
activation has been observed in many hematopoietic and non-hematopoietic cell 
types upon appropriate stimuli. p38alpha kinase is involved in the biosynthesis 
of the cytokines tumor necrosis factor-alpha and interleukin-1beta at the 
translational and transcriptional level. MAPK p38alpha represents a point of 
convergence for multiple signaling processes that are activated during 
inflammation, making it a key potential target for the modulation of cytokine 
production. The discovery and publication of p38alpha and a 
pyridinyl-imidazole-based p38alpha inhibitor initiated a huge effort by many 
companies to develop p38alpha inhibitors as potential treatments for 
inflammatory diseases. Herein, a brief overview is provided of the discovery and 
development of AMG-548 (Amgen Inc), a selective and efficacious p38alpha 
inhibitor, and its pharmacodynamic effects in a first-in-human study. Data from 
a phase I multidose clinical trial are also included. In addition, other 
p38alpha inhibitors that have advanced to clinical trials over the last three 
years are discussed, such as BIRB-796 (Boehringer Ingelheim Pharmaceuticals 
Inc), SCIO-469 and SCIO-323 (Scios Inc), and VX-702 (Vertex Pharmaceuticals 
Inc/Kissei Pharmaceutical Co).