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

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journal contribution
posted on 22.10.2009, 00:00 by Nicola M. Aston, Paul Bamborough, Jacqueline B. Buckton, Christopher D. Edwards, Duncan S. Holmes, Katherine L. Jones, Vipulkumar K. Patel, Penny A. Smee, Donald O. Somers, Giovanni Vitulli, Ann L. Walker
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.