p38α Mitogen-Activated Protein Kinase Inhibitors: Optimization of a Series of Biphenylamides to Give a Molecule Suitable for Clinical Progression

p38α MAP kinase is a key anti-inflammatory target for rheumatoid arthritis, influencing biosynthesis of pro-inflammatory cytokines TNFα and IL-1β at a translational and transcriptional level. In this paper, we describe how we have optimized a series of novel p38α/β inhibitors using crystal structures of our inhibitors bound to p38α, classical medicinal chemistry, and modeling of virtual libraries to derive a molecule suitable for progression into clinical development.