p38α Mitogen-Activated Protein Kinase Inhibitors: Optimization of a Series of Biphenylamides to Give a Molecule Suitable for Clinical Progression
Journal of Medicinal Chemistry2009Vol. 52(20), pp. 6257–6269
Citations Over TimeTop 17% of 2009 papers
Natalie E. Aston, Paul Bamborough, Jacqueline B. Buckton, Christopher D. Edwards, Duncan S. Holmes, Katherine L. Jones, Vipulkumar K. Patel, Penny A. Smee, D.O. Somers, Giovanni Vitulli, Ann L. Walker
Abstract
p38alpha MAP kinase is a key anti-inflammatory target for rheumatoid arthritis, influencing biosynthesis of pro-inflammatory cytokines TNFalpha and IL-1beta at a translational and transcriptional level. In this paper, we describe how we have optimized a series of novel p38alpha/beta inhibitors using crystal structures of our inhibitors bound to p38alpha, classical medicinal chemistry, and modeling of virtual libraries to derive a molecule suitable for progression into clinical development.
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