Discovery of potent, selective, and orally bioavailable inhibitors of interleukin-1 receptor-associate kinase-4

Bioorg Med Chem Lett. 2015 Dec 1;25(23):5546-50. doi: 10.1016/j.bmcl.2015.10.060. Epub 2015 Oct 23.

Abstract

In this Letter, we report the continued optimization of the N-acyl-2-aminobenzimidazole series, focusing in particular on the N-alkyl substituent and 5-position of the benzimidazole based on the binding mode and the early SAR. These efforts led to the discovery of 16, a highly potent, selective, and orally bioavailable inhibitor of IRAK-4.

Keywords: Inflammation; Interleukin-1 receptor-associate kinase-4; N-Acyl-2-aminobenzimidazole.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzimidazoles / chemistry
  • Drug Discovery*
  • Enzyme Activation / drug effects
  • Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
  • Molecular Structure
  • Protein Binding / drug effects
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Protein Kinase Inhibitors
  • 2-aminobenzimidazole
  • Interleukin-1 Receptor-Associated Kinases