Novel Class of Colony-Stimulating Factor 1 Receptor Kinase Inhibitors Based on an <i>o</i>-Aminopyridyl Alkynyl Scaffold as Potential Treatment for Inflammatory Disorders
Zhicheng Xie, Bing Wu, Yingqiang Liu, Wenming Ren, Linjiang Tong, Caigui Xiang, Aihuan Wei, Yuanzhuo Gao, Limin Zeng, Hua Xie, Wei Tang, Youhong Hu
Abstract
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.