Novel Class of Colony-Stimulating Factor 1 Receptor Kinase Inhibitors Based on an o-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

doi:10.1021/acs.jmedchem.9b01912

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

J Med Chem. 2020 Feb 13;63(3):1397-1414. doi: 10.1021/acs.jmedchem.9b01912. Epub 2020 Jan 14.

Authors

Zhicheng Xie^{1

2}, Bing Wu^{3

2}, Yingqiang Liu^{1

4}, Wenming Ren¹, Linjiang Tong^{1

2}, Caigui Xiang^{3

2}, Aihuan Wei¹, Yuanzhuo Gao^{3

2}, Limin Zeng¹, Hua Xie^{1

2}, Wei Tang^{3

2}, Youhong Hu^{1

2}

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica , Chinese Academy of Sciences , No. 555 Zu-Chong-Zhi Road, Zhangjiang Hi-Tech Park , Shanghai 201203 , China.
² University of Chinese Academy of Sciences , 19 Yuquan Road , Beijing 100049 , China.
³ Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica , Chinese Academy of Sciences , Shanghai 201203 , China.
⁴ School of Pharmacy , Fudan University , Shanghai 201203 , China.

PMID: 31934767
DOI: 10.1021/acs.jmedchem.9b01912

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkynes / chemical synthesis
Alkynes / pharmacokinetics
Alkynes / therapeutic use*
Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / pharmacokinetics
Anti-Inflammatory Agents / therapeutic use*
Female
Inflammation / chemically induced
Inflammation / drug therapy*
Lipopolysaccharides
Mice
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / therapeutic use*
Pyridines / chemical synthesis
Pyridines / pharmacokinetics
Pyridines / therapeutic use*
RAW 264.7 Cells
Rats, Sprague-Dawley
Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
Receptor, Macrophage Colony-Stimulating Factor / metabolism
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / pharmacokinetics
Small Molecule Libraries / therapeutic use
Structure-Activity Relationship

Substances

Alkynes
Anti-Inflammatory Agents
Lipopolysaccharides
Protein Kinase Inhibitors
Pyridines
Small Molecule Libraries
Receptor, Macrophage Colony-Stimulating Factor