Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation

Bioorg Med Chem Lett. 2017 Jun 15;27(12):2721-2726. doi: 10.1016/j.bmcl.2017.04.050. Epub 2017 Apr 18.

Abstract

Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.

Keywords: IRAK4; Inflammatory disease; Kinase inhibitor; Quinazoline; Serine-threonine kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • High-Throughput Screening Assays
  • Imidazoles / pharmacology
  • Inflammation / drug therapy*
  • Inflammation / enzymology
  • Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / biosynthesis
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Quinazolines / administration & dosage
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Rats
  • Rats, Inbred Lew
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Interleukin-6
  • Protein Kinase Inhibitors
  • Quinazolines
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • resiquimod