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 |
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Authors: | Kazutaka Ikegashira Taku Ikenogami Takayuki Yamasaki Takahiro Oka Yasunori Hase Naoki Miyagawa Koji Inagaki Iichiro Kawahara Yoshihisa Koga Hiromasa Hashimoto |
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Institution: | Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan |
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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. |
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Keywords: | CSF-1R Type II inhibitor Azetidine scaffold |
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