Novel Class of Colony-Stimulating Factor 1 Receptor Kinase Inhibitors Based on an o-Aminopyridyl Alkynyl Scaffold as Potential Treatment for Inflammatory Disorders.,Journal of Medicinal Chemistry

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Novel Class of Colony-Stimulating Factor 1 Receptor Kinase Inhibitors Based on an o-Aminopyridyl Alkynyl Scaffold as Potential Treatment for Inflammatory Disorders.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-14 , DOI: 10.1021/acs.jmedchem.9b01912
Zhicheng Xie _{1,

2} , Bing Wu _{2,

3} , Yingqiang Liu _{1,

4} , Wenming Ren ₁ , Linjiang Tong _{1,

2} , Caigui Xiang _{2,

3} , Aihuan Wei ₁ , Yuanzhuo Gao _{2,

3} , Limin Zeng ₁ , Hua Xie _{1,

2} , Wei Tang _{2,

3} , Youhong Hu _{1,

2}

Affiliation

Colony-stimulating factor 1 receptor (CSF-1R) is involved in inflammatory disorders as well as in many types of cancer. Based on high-throughput screening and docking results, we performed a detailed structure-activity-relationship study, leading to the discovery of a new series of compounds with nanomolar IC50 values against CSF-1R without the inhibition of fibroblast growth factor receptors. One of the most promising hits, compound 29, potently inhibited CSF-1R kinase with an IC50 value of 0.7 nM, while it showed no inhibition to the same family member FMS-like tyrosine kinase 3. Compound 29 displayed excellent anti-inflammatory effects against RAW264.7 macrophages indicated by significant inhibition against the activation of the CSF-1R pathway with low cytotoxicity. In addition, compound 29 exhibited strong in vivo anti-inflammatory efficacy alongside favorable drug characteristics. This novel compound 29 may serve as a new drug candidate with promising applications in inflammatory disorders.

中文翻译：

基于o-氨基吡啶基炔基支架的新型类集落刺激因子1受体激酶抑制剂作为潜在的炎症性疾病治疗。

集落刺激因子1受体（CSF-1R）参与炎症性疾病以及许多类型的癌症。基于高通量筛选和对接结果，我们进行了详细的结构-活性-关系研究，从而发现了一系列具有针对CSF-1R的纳摩尔IC50值且不抑制成纤维细胞生长因子受体的新化合物。最有前途的命中化合物之一化合物29可有效抑制CSF-1R激酶，IC50值为0.7 nM，而对相同家族成员的FMS样酪氨酸激酶3则没有抑制作用。化合物29对ASF表现出出色的抗炎作用RAW264.7巨噬细胞显示出对CSF-1R途径活化的显着抑制，细胞毒性较低。此外，化合物29显示出强的体内抗炎功效以及有利的药物特性。该新型化合物29可以用作在炎性疾病中有希望的应用的新药物候选物。

更新日期：2020-01-15

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