Back to Search
Start Over
Discovery of Pyrrolopyridine−Pyridone Based Inhibitors of Met Kinase: Synthesis, X-ray Crystallographic Analysis, and Biological Activities
Discovery of Pyrrolopyridine−Pyridone Based Inhibitors of Met Kinase: Synthesis, X-ray Crystallographic Analysis, and Biological Activities
- Source :
- Journal of Medicinal Chemistry. 51:5330-5341
- Publication Year :
- 2008
- Publisher :
- American Chemical Society (ACS), 2008.
-
Abstract
- Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.
- Subjects :
- Male
Pyridones
medicine.drug_class
Stereochemistry
Antineoplastic Agents
Carboxamide
Crystallography, X-Ray
Inhibitory Concentration 50
Mice
Structure-Activity Relationship
Cell Line, Tumor
Proto-Oncogene Proteins
Drug Discovery
medicine
Animals
Humans
Transferase
Structure–activity relationship
Receptors, Growth Factor
Binding site
Protein Kinase Inhibitors
Cell Proliferation
chemistry.chemical_classification
Mice, Inbred BALB C
Kinase
Phosphotransferases
Proto-Oncogene Proteins c-met
Vascular Endothelial Growth Factor Receptor-2
Enzyme
fms-Like Tyrosine Kinase 3
Biochemistry
chemistry
Microsomes, Liver
Molecular Medicine
Signal transduction
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 51
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....f58a9baa70cfbe1d4ab37df5d6a6a243
- Full Text :
- https://doi.org/10.1021/jm800476q