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

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 <b>29</b>, 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 <b>29</b> 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 <b>29</b> exhibited strong in vivo anti-inflammatory efficacy alongside favorable drug characteristics. This novel compound <b>29</b> may serve as a new drug candidate with promising applications in inflammatory disorders.