The Discovery of Novel Chemotypes of p38 Kinase Inhibitors

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 discovered by xray crystallographic and virtual screening was announced. Finally, throughout the life span of p38 drug discovery programs significant medicinal chemistry effort has continually been placed on the design of new inhibitors from known chemotypes using molecular modeling, protein crystallography, hybrid design and simply sound intuition. Indeed, the search for p38 kinase inhibitors offers an excellent historical perspective as to how technological changes that have taken place in the pharmaceutical industry over the last decade, have affected the ways in which new leads are discovered and advanced. It is the intent of this review to highlight the discoveries of novel p38 chemotypes, emphasizing where possible the key technologies used in the discoveries and the knowledge gained from each discovery.