Novel 7-formyl-naphthyridyl-ureas derivatives as potential selective FGFR4 inhibitors: Design, synthesis, and biological activity studies

Chang'an Sun; Lei Fang; Xiaobing Zhang; Peng Gao; Shaohua Gou

doi:10.1016/j.bmc.2019.04.018

Novel 7-formyl-naphthyridyl-ureas derivatives as potential selective FGFR4 inhibitors: Design, synthesis, and biological activity studies

Bioorg Med Chem. 2019 May 15;27(10):1932-1941. doi: 10.1016/j.bmc.2019.04.018. Epub 2019 Apr 10.

Authors

Chang'an Sun¹, Lei Fang², Xiaobing Zhang¹, Peng Gao³, Shaohua Gou⁴

Affiliations

¹ Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Hansoh Pharmaceutical Group CO., LTD., Lianyungang 222000, China.
² Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin 541004, China. Electronic address: lei.fang@seu.edu.cn.
³ Jiangsu Hansoh Pharmaceutical Group CO., LTD., Lianyungang 222000, China.
⁴ Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address: sgou@seu.edu.cn.

PMID: 30987781
DOI: 10.1016/j.bmc.2019.04.018

Abstract

Total twenty-five 7-formyl-naphthyridyl-urea derivatives were designed, synthesized and evaluated for their inhibition of FGFR4 kinase and antitumor activity. The pharmacological data indicated that most of the tested compounds showed high selectivity towards FGFR4 kinase and could significantly inhibit FGFR4 and the tumor cells lines with the high expression of FGFR4. In particular, compounds 6f, 6g, 6h, 6l, 6m and 6s showed a good performance in pharmacokinetic tests. When tested in mice, the representative compound 6f was found to have good pharmacokinetic parameters, low toxicity, and better tumor inhibiting activity in vivo.

Keywords: Antitumor; FGFR4; Pharmacokinetic profile; Selectivity.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Cell Line, Tumor
Cell Survival / drug effects
Drug Design*
Drug Screening Assays, Antitumor
Female
Half-Life
Humans
Male
Mice
Mice, Nude
Neoplasms / drug therapy
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Receptor, Fibroblast Growth Factor, Type 4 / antagonists & inhibitors*
Receptor, Fibroblast Growth Factor, Type 4 / metabolism
Structure-Activity Relationship
Transplantation, Heterologous
Urea / analogs & derivatives*
Urea / metabolism
Urea / pharmacology

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Urea
FGFR4 protein, human
Receptor, Fibroblast Growth Factor, Type 4