Imidazo[1,5-a]quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid arthritis

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6258-63. doi: 10.1016/j.bmcl.2011.09.008. Epub 2011 Sep 10.

Abstract

Imidazo[1,5-a]quinoxalines were synthesized that function as irreversible Bruton's tyrosine kinase (BTK) inhibitors. The syntheses and SAR of this series of compounds are presented as well as the X-ray crystal structure of the lead compound 36 in complex with a gate-keeper variant of ITK enzyme. The lead compound showed good in vivo efficacy in preclinical RA models.

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Arthritis, Rheumatoid / drug therapy*
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Quinoxalines / chemistry
  • Quinoxalines / pharmacology*

Substances

  • Protein Kinase Inhibitors
  • Quinoxalines
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human