Optimization of an azetidine series as inhibitors of colony stimulating factor-1 receptor (CSF-1R) Type II to lead to the clinical candidate JTE-952

Bioorg Med Chem Lett. 2019 Apr 1;29(7):873-877. doi: 10.1016/j.bmcl.2019.02.006. Epub 2019 Feb 7.

Abstract

Optimization of novel azetidine compounds, which we had found as colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors, provided JTE-952 as a clinical candidate with high cellular activity (IC50 = 20 nM) and good pharmacokinetics profile. JTE-952 was also effective against a mouse collagen-induced model of arthritis (mouse CIA-model). Additionally, the X-ray co-crystal structure of JTE-952 with CSF-1R protein was shown to be a Type II inhibitor, and the kinase panel assay indicated that JTE-952 had high kinase selectivity.

Keywords: Azetidine scaffold; CSF-1R; Type II inhibitor.

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy*
  • Azetidines / chemistry*
  • Azetidines / pharmacology
  • Collagen / toxicity
  • Gene Expression Regulation / drug effects
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / pharmacology
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors*

Substances

  • Azetidines
  • Csf1r protein, mouse
  • JTE-952
  • Protein Kinase Inhibitors
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • azetidine
  • Collagen