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.
Kazutaka Ikegashira  1 ,  Taku Ikenogami  1 ,  Takayuki Yamasaki  1 ,  Takahiro Oka  1 ,  Yasunori Hase  1 ,  Naoki Miyagawa  1 ,  Koji Inagaki  1 ,  Iichiro Kawahara  1 ,  Yoshihisa Koga  1 ,  Hiromasa Hashimoto  1
Affiliations
  • 1. Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
PMID: 30755337 DOI: 10.1016/j.bmcl.2019.02.006
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.
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