p38 Inhibitors: beyond pyridinylimidazoles

Abstract

Since the discovery of p38 mitogen-activated protein kinase (MAPK) as a potential intracellular modulator that regulates the crucial biosynthesis and functions of pro-inflammatory cytokines (e.g., TNF-α and IL-1β), numerous groups have disclosed their efforts to find small-molecule p38 inhibitors as potential therapeutic agents for the treatment of inflammatory diseases such as rheumatoid arthritis (RA), Crohn’s disease (CD) and psoriasis. Although greater selectivity has been achieved with these newly disclosed series, their safety profile after chronic treatment remains a question to be answered in human clinical trials. The p38 inhibitors that have been disclosed in the recent patent literature (2000 – 2004) are summarised here. These compounds will be classified into series based on their intrinsic structures and by their binding modes, as revealed by either crystallography or molecular modelling.

Keywords::

• cytokine biosynthesis inhibitor
• cytokine-mediated disease
• IL-1β
• inflammation
• p38 kinase inhibitor
• p38 mitogen-activated protein kinase (MAPK)
• TNF-α