Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Bioorg Med Chem Lett. 2019 Apr 1;29(7):873-877. doi: 10.1016/j.bmcl.2019.02.006. Epub 2019 Feb 7.
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 (IC = 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.
我们发现新型氮杂环丁烷化合物是集落刺激因子-1 受体（CSF-1R）Ⅱ型抑制剂，通过对其优化得到临床候选药物 JTE-952，该化合物具有高细胞活性（IC=20nM）和良好的药代动力学特性。JTE-952 对胶原诱导的关节炎小鼠模型（mouse CIA-model）也具有疗效。此外，JTE-952 与 CSF-1R 蛋白的 X 射线共晶结构显示为Ⅱ型抑制剂，激酶谱分析表明 JTE-952 具有很高的激酶选择性。
