p38 MAP kinase inhibitors. Part 5: discovery of an orally bio-available and highly efficacious compound based on the 7-amino-naphthyridone scaffold

Bioorg Med Chem Lett. 2006 Oct 15;16(20):5468-71. doi: 10.1016/j.bmcl.2006.06.084. Epub 2006 Sep 1.

Abstract

A new sub-class of p38 inhibitors represented by 7-amino-naphthyridone have been discovered. Benchmark compound 16 potently inhibited p38 in vitro, was functionally active, and displayed excellent pharmacokinetic profiles in two animal species. Compound 16 reduced inflammation in animal disease models at EC(50) doses as low as 0.2mpk.

MeSH terms

  • Administration, Oral
  • Animals
  • Binding Sites
  • Biological Availability
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics*
  • Humans
  • In Vitro Techniques
  • Lipopolysaccharides / pharmacology
  • Macaca mulatta
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Microsomes, Liver / drug effects
  • Molecular Structure
  • Monocytes / drug effects
  • Naphthyridines / administration & dosage*
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacokinetics*
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*

Substances

  • 7-amino-5-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-1,6-naphthyridin-1H-2-one
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Naphthyridines
  • Tumor Necrosis Factor-alpha
  • p38 Mitogen-Activated Protein Kinases