Anilino-monoindolylmaleimides as potent and selective JAK3 inhibitors

Bioorg Med Chem Lett. 2014 Feb 15;24(4):1116-21. doi: 10.1016/j.bmcl.2014.01.001. Epub 2014 Jan 9.

Abstract

We designed a series of anilino-indoylmaleimides based on structural elements from literature JAK3 inhibitors 3 and 4, and our lead 5. These new compounds were tested as inhibitors of JAKs 1, 2 and 3 and TYK2 for therapeutic intervention in rheumatoid arthritis (RA). Our requirements, based on current scientific rationale for optimum efficacy against RA with reduced side effects, was for potent, mixed JAK1 and 3 inhibition, and selectivity over JAK2. Our efforts yielded a potent JAK3 inhibitor 11d and its eutomer 11e. These compounds were highly selective for inhibition of JAK3 over JAK2 and TYK. The compounds displayed only modest JAK1 inhibition.

Keywords: Anilino-monoindolylmaleimide; JAK1 inhibitor; JAK2 selective inhibitor; JAK3 inhibitor; Rheumatoid arthritis.

MeSH terms

  • Aniline Compounds / chemical synthesis
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Janus Kinase 3 / antagonists & inhibitors*
  • Janus Kinase 3 / metabolism
  • Maleimides / chemical synthesis
  • Maleimides / chemistry
  • Maleimides / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Aniline Compounds
  • Maleimides
  • Protein Kinase Inhibitors
  • JAK3 protein, human
  • Janus Kinase 3
  • aniline