p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression.

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 20 Pg. 6257-69 (Oct 22 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19772287 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Biphenyl Compounds
• Protein Kinase Inhibitors
• diphenyl
• Mitogen-Activated Protein Kinase 14

Topics

• Administration, Oral
• Amides (administration & dosage, chemistry, pharmacology, therapeutic use)
• Animals
• Arthritis, Experimental (drug therapy)
• Biphenyl Compounds (chemistry)
• Drug Discovery
• Humans
• Mice
• Mitogen-Activated Protein Kinase 14 (antagonists & inhibitors, chemistry)
• Models, Molecular
• Molecular Conformation
• Protein Kinase Inhibitors (administration & dosage, chemistry, pharmacology, therapeutic use)
• Rats