Current Topics in Medicinal Chemistry - Volume 5, Issue 10, 2005

The last several years have seen an explosion of interest in developing inhibitors to kinases found critical to the pathogenesis of disease. Improvements in screening techniques, surveying kinase selectivity and understanding the side-effects of kinase inhibition have made targeting kinases for therapeutic intervention more attainable. Development of p38α MAP kinase inhibitors for the treatment of inflammatory dise Read More

The p38 kinase plays a central role in inflammation, and it has been the subject of extensive efforts in both basic research and drug discovery. This review summarizes the biology of the p38 kinase with a focus on its role in inflammation. The p38 kinase regulates the production of key inflammatory mediators, including TNFα, IL-1β, and COX- 2. In addition, p38 also acts downstream of cytokines such as TNFα, mediating Read More

Inhibitors of p38 MAP kinases show promise for the treatment of inflammatory and immunological disorders and some cancers. There is a substantial body of experimental evidence across several organ systems suggesting that p38 also mediates developmental, differentiation and proliferation processes. As a consequence of the wide-ranging regulatory role of p38 kinase in diverse cellular processes, the possibility Read More

The p38 MAP kinases are a family of serine/threonine protein kinases that play a key role in cellular pathways leading to pro-inflammatory responses. We have developed and implemented a method for rapidly identifying and optimizing potent and selective p38α inhibitors, which is amenable to other targets and target classes. A diverse library of druggable, purified and quantitated molecules was assembled and sta Read More

In the late 1970s and the early 1980s the initial p38 chemotype, the triaryl imidazoles, was discovered as an off-target effect during the development of cyclooxygenase and 5-lipoxygenase inhibitors long before the identity of the p38 kinase was known. During the last 10 years a number of novel p38 chemotypes were discovered via high throughput screening. More recently, the first series of p38 inhibitors discov Read More

The discovery and development of selective, efficacious, and safe small molecule p38 mitogen-activated protein kinase inhibitors for the treatment of inflammatory diseases remains the focus of many pharmaceutical research programs. Advances in small molecule p38 inhibitor design in potency and oral efficacy have been accelerated with the large number of available inhibitor-enzyme x-ray structures. These advances Read More

The initial disclosure of tri-substituted imidazole-based drug molecules such as 1 for inhibition of p38 MAP kinase by SmithKline Beecham (SB) sparked an effort in this area at Merck and other pharmaceutical research establishments. Although analogs in this class have shown good inhibitory properties against p38 MAP kinase, their selectivity profile were modest and left much room for improvement. Attempts to dis Read More

Small molecule inhibition of protein kinases in the treatment of significant diseases such as cancer, Alzheimer's disease, diabetes, and rheumatoid arthritis has attracted significant attention over the past two decades and has clearly become one of the most significant challenges for drug discovery in the 21st century. While the recent identification of 518 different kinases in the human genome has offered a wealth of oppo Read More

p38 mitogen activated protein (MAP) kinase remains the most compelling therapeutic target for oral drug intervention for a wide range of autoimmune disorders based on the central role this enzyme plays in inflammatory cell signaling. Efforts to discover inhibitors of p38 suitable for clinical investigation have continued to escalate in part due to the incredible diversity of unique chemotypes reported to inhibit the enzy Read More