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

J Med Chem. 2009 Oct 22;52(20):6257-69. doi: 10.1021/jm9004779.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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