Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors

Bioorg Med Chem Lett. 2017 Nov 1;27(21):4908-4913. doi: 10.1016/j.bmcl.2017.09.029. Epub 2017 Sep 18.

Abstract

The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.

Keywords: 4,6-Diaminonicotinamide; Autoimmune disease; IRAK4; Rheumatoid arthritis.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Humans
  • Inhibitory Concentration 50
  • Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Janus Kinase 3 / chemistry
  • Janus Kinase 3 / metabolism
  • Molecular Conformation
  • Molecular Dynamics Simulation
  • Niacinamide / chemistry*
  • Niacinamide / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Structure, Tertiary
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Niacinamide
  • JAK3 protein, human
  • Janus Kinase 3
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases