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Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors
- Source :
- Bioorganicmedicinal chemistry letters. 25(17)
- Publication Year :
- 2015
-
Abstract
- Based on a putative binding mode of quizartinib (AC220, 1), a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clinical development, we have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compound (6s) in tumor xenograft model for further preclinical development.
- Subjects :
- Clinical Biochemistry
Pharmaceutical Science
Aminopyridines
Antineoplastic Agents
Pharmacology
Biochemistry
chemistry.chemical_compound
In vivo
Drug Discovery
Humans
Molecular Biology
Tumor xenograft
Quizartinib
Cell Proliferation
CYP3A4
Dose-Response Relationship, Drug
Aryl
Organic Chemistry
Xenograft Model Antitumor Assays
chemistry
fms-Like Tyrosine Kinase 3
Tyrosine Kinase 3
Fms-Like Tyrosine Kinase 3
Molecular Medicine
Subjects
Details
- ISSN :
- 14643405
- Volume :
- 25
- Issue :
- 17
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry letters
- Accession number :
- edsair.doi.dedup.....109fecdca0b1b404a04804a76856a998