Initial optimization and series evolution of diaminopyrimidine inhibitors of interleukin-1 receptor associated kinase 4

Bioorg Med Chem Lett. 2015 Aug 15;25(16):3203-7. doi: 10.1016/j.bmcl.2015.05.097. Epub 2015 Jun 6.

Abstract

IRAK4 plays a key role in TLR/IL-1 signaling. Previous efforts identified a series of aminopyrimidine IRAK4 inhibitors that possess good potency, but modest kinase selectivity. Exploration of substituents at the C-2 and C-5 positions generated compounds that maintained IRAK4 potency and improved kinase selectivity. Additionally, it was found that the pyrimidine core could be replaced with a pyridine and still retain potency and kinase selectivity. The optimization efforts led to compound 26 which had an IRAK4 IC50 of 0.7 nM, an IC50 of 55 nM on THP-1 cells stimulated with LPS, a TLR4 agonist, and greater than 100-fold selectivity versus 96% of a panel of 306 kinases.

Keywords: Aminopyrimidine; IRAK4; Inflammation; Kinase; Structure activity relationships.

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Cell Line
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
  • Lipopolysaccharides / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • Substrate Specificity
  • Toll-Like Receptor 4 / antagonists & inhibitors

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Pyrimidines
  • Toll-Like Receptor 4
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases