Naphthyridines as novel BET family bromodomain inhibitors

ChemMedChem. 2014 Mar;9(3):580-9. doi: 10.1002/cmdc.201300259. Epub 2013 Sep 2.


Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including gene transcription and mRNA elongation. Inhibitors of the bromodomain and extra-terminal (BET) proteins BRD2-4 and T, which prevent bromodomain binding to acetyl-modified histone tails, have shown therapeutic promise in several diseases. We report here the discovery of 1,5-naphthyridine derivatives as potent inhibitors of the BET bromodomain family with good cell activity and oral pharmacokinetic parameters. X-ray crystal structures of naphthyridine isomers have been solved and quantum mechanical calculations have been used to explain the higher affinity of the 1,5-isomer over the others. The best compounds were progressed in a mouse model of inflammation and exhibited dose-dependent anti-inflammatory pharmacology.

Keywords: BET family bromodomains inhibitors; epigenetic readers; inflammation; naphthyridines.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Chromosomal Proteins, Non-Histone
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Histones / chemistry
  • Histones / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Molecular Structure
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacology*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Tertiary / drug effects
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism


  • Anti-Inflammatory Agents, Non-Steroidal
  • BRDT protein, mouse
  • Brd2 protein, mouse
  • Brd3 protein, mouse
  • Brd4 protein, mouse
  • Chromosomal Proteins, Non-Histone
  • Histones
  • Naphthyridines
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Transcription Factors
  • Protein Serine-Threonine Kinases