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Design, Synthesis and Biological Evaluation of 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors.
- Source :
-
Molecules (Basel, Switzerland) [Molecules] 2016 Oct 23; Vol. 21 (10). Date of Electronic Publication: 2016 Oct 23. - Publication Year :
- 2016
-
Abstract
- Tyrosine kinase fibroblast growth factor receptor (FGFR), which is aberrant in various cancer types, is a promising target for cancer therapy. Here we reported the design, synthesis, and biological evaluation of a new series of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-4-substituted-1 H -indazole derivatives as potent FGFR inhibitors. The compound 6-(2,6-dichloro-3,5-dimethoxyphenyl)- N -phenyl-1 H -indazole-4-carboxamide ( 10a ) was identified as a potent FGFR1 inhibitor, with good enzymatic inhibition. Further structure-based optimization revealed that 6-(2,6-dichloro-3,5-dimethoxyphenyl)- N -(3-(4-methylpiperazin-1-yl)phenyl)-1 H -indazole-4-carboxamide ( 13a ) is the most potent FGFR1 inhibitor in this series, with an enzyme inhibitory activity IC <subscript>50</subscript> value of about 30.2 nM.
- Subjects :
- Cell Line, Tumor
Drug Design
Humans
Indazoles chemistry
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacology
Receptor, Fibroblast Growth Factor, Type 1 antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 1 chemistry
Receptors, Fibroblast Growth Factor chemistry
Structure-Activity Relationship
Indazoles chemical synthesis
Indazoles pharmacology
Receptors, Fibroblast Growth Factor antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1420-3049
- Volume :
- 21
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecules (Basel, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 27782099
- Full Text :
- https://doi.org/10.3390/molecules21101407