Efforts towards the optimization of a bi-aryl class of potent IRAK4 inhibitors

Bioorg Med Chem Lett. 2016 Sep 1;26(17):4250-5. doi: 10.1016/j.bmcl.2016.07.048. Epub 2016 Jul 22.

Abstract

IRAK4 has been identified as potential therapeutic target for inflammatory and autoimmune diseases. Herein we report the identification and initial SAR studies of a new class of pyrazole containing IRAK4 inhibitors designed to expand chemical diversity and improve off target activity of a previously identified series. These compounds maintain potent IRAK4 activity and desirable ligand efficiency. Rat clearance and a variety of off target activities were also examined, resulting in encouraging data with tractable SAR.

Keywords: IRAK4; Inflammation; Interleukin receptor-associated kinases; SAR; Toll-like receptors.

MeSH terms

  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Half-Life
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Ligands
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Structure, Tertiary
  • Pyrazoles / chemistry*
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacokinetics
  • Rats
  • Structure-Activity Relationship

Substances

  • Ligands
  • Protein Kinase Inhibitors
  • Pyrazoles
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases