Uesato Naofumi, Miyagawa Naoki, Inagaki Koji, Kakefuda Reina, Kitagawa Yoshihiro, Matsuo Yushi, Yamaguchi Takayuki, Hata Takahiro, Ikegashira Kazutaka, Matsushita Mutsuyoshi
Central Pharmaceutical Research Institute, Japan Tobacco Inc.
Biol Pharm Bull. 2020;43(2):325-333. doi: 10.1248/bpb.b19-00694.
Colony stimulating factor 1 (CSF1) receptor (CSF1R) is a receptor protein-tyrosine kinase specifically expressed in monocyte-lineage cells, such as monocytes and macrophages. In this study, we characterized the pharmacological properties of an azetidine compound, JTE-952 ((2S)-3-{[2-({3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidine-1-yl}carbonyl)pyridin-4-yl]methoxy}propane-1,2-diol), which is a novel CSF1R tyrosine kinase inhibitor. JTE-952 potently inhibited human CSF1R kinase activity, with a half maximal inhibitory concentration of 11.1 nmol/L, and inhibited the phosphorylation of CSF1R in human macrophages and the CSF1-induced proliferation of human macrophages. It also inhibited human tropomyosin-related kinase A activity, but only at concentrations 200-fold higher than that required to inhibit the activity of CSF1R in inducing the proliferation of human macrophages. JTE-952 displayed no marked inhibitory activity against other kinases. JTE-952 potently inhibited lipopolysaccharide-induced proinflammatory cytokine production by human macrophages and in whole blood. JTE-952 (≥3 mg/kg given orally) also significantly attenuated the CSF1-induced priming of lipopolysaccharide-induced tumor necrosis factor-alpha production in mice and arthritis severity in a mouse model of collagen-induced arthritis. Taken together, these results indicate that JTE-952 is an orally available compound with potent and specific inhibitory activity against CSF1R, both in vitro and in vivo. JTE-952 is a potentially clinically useful agent for various human inflammatory diseases, including rheumatoid arthritis.
集落刺激因子1（CSF1）受体（CSF1R）是一种受体蛋白酪氨酸激酶，特异性表达于单核细胞系细胞，如单核细胞和巨噬细胞。在本研究中，我们对氮杂环丁烷化合物JTE-952（(2S)-3-{[2-({3-[4-(4-环丙基苄氧基)-3-甲氧基苯基]氮杂环丁烷-1-基}羰基)吡啶-4-基]甲氧基}丙烷-1,2-二醇）的药理学特性进行了表征，它是一种新型的CSF1R酪氨酸激酶抑制剂。JTE-952能有效抑制人CSF1R激酶活性，半数最大抑制浓度为11.1 nmol/L，并能抑制人巨噬细胞中CSF1R的磷酸化以及CSF1诱导的人巨噬细胞增殖。它还能抑制人原肌球蛋白相关激酶A的活性，但仅在比抑制CSF1R诱导人巨噬细胞增殖活性所需浓度高200倍的浓度下才起作用。JTE-952对其他激酶无明显抑制活性。JTE-952能有效抑制人巨噬细胞和全血中脂多糖诱导的促炎细胞因子产生。JTE-952（口服给药≥3 mg/kg）还能显著减轻CSF1诱导的小鼠脂多糖诱导的肿瘤坏死因子-α产生的启动作用以及胶原诱导性关节炎小鼠模型中的关节炎严重程度。综上所述，这些结果表明JTE-952是一种口服可用的化合物，在体外和体内对CSF1R均具有强效且特异性的抑制活性。JTE-952是一种对包括类风湿关节炎在内的各种人类炎症性疾病具有潜在临床应用价值的药物。
