Imidazoquinoxaline Src-family kinase p56Lck inhibitors: SAR, QSAR, and the discovery of (S)-N-(2-chloro-6-methylphenyl)-2-(3-methyl-1-piperazinyl)imidazo- [1,5-a]pyrido[3,2-e]pyrazin-6-amine (BMS-279700) as a potent and orally active inhibitor with excellent in vivo antiinflammatory activity

J Med Chem. 2004 Aug 26;47(18):4517-29. doi: 10.1021/jm030217e.

Abstract

A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56Lck and T cell proliferation have been discovered. Subsequent SAR studies led to the identification of compound 4 (BMS-279700) as an orally active lead candidate that blocks the production of proinflammatory cytokines (IL-2 and TNFalpha) in vivo. In addition, an expanded set of imidazoquinoxalines provided several descriptive QSAR models highlighting the influence of significant steric and electronic features. The H-bonding (Met319) contribution to observed binding affinities within a tightly congeneric series was found to be significant.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology
  • Biological Availability
  • Cytokines / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Female
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Pyrazines / chemistry
  • Pyrazines / pharmacology
  • Quantitative Structure-Activity Relationship*
  • Quinoxalines / chemistry*
  • Quinoxalines / pharmacokinetics*
  • Quinoxalines / pharmacology
  • src-Family Kinases / antagonists & inhibitors

Substances

  • Anti-Inflammatory Agents
  • BMS279700
  • Cytokines
  • Enzyme Inhibitors
  • Pyrazines
  • Quinoxalines
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • src-Family Kinases