Pyrazole urea-based inhibitors of p38 MAP kinase: from lead compound to clinical candidate

J Med Chem. 2002 Jul 4;45(14):2994-3008. doi: 10.1021/jm020057r.

Abstract

We report on a series of N-pyrazole, N'-aryl ureas and their mode of binding to p38 mitogen activated protein kinase. Importantly, a key binding domain that is distinct from the adenosine 5'-triphoshate (ATP) binding site is exposed when the conserved activation loop, consisting in part of Asp168-Phe169-Gly170, adopts a conformation permitting lipophilic and hydrogen bonding interactions between this class of inhibitors and the protein. We describe the correlation of the structure-activity relationships and crystallographic structures of these inhibitors with p38. In addition, we incorporated another binding pharmacophore that forms a hydrogen bond at the ATP binding site. This modification affords significant improvements in binding, cellular, and in vivo potencies resulting in the selection of 45 (BIRB 796) as a clinical candidate for the treatment of inflammatory diseases.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Binding, Competitive
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Female
  • Fluorescence
  • Humans
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Models, Molecular
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology
  • Protein Binding
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Urea / analogs & derivatives*
  • Urea / chemical synthesis*
  • Urea / chemistry
  • Urea / pharmacology
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Naphthalenes
  • Pyrazoles
  • Tumor Necrosis Factor-alpha
  • Urea
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • doramapimod