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Design and optimization of a series of 1-sulfonylpyrazolo[4,3-b]pyridines as selective c-Met inhibitors
- Source :
- Journal of medicinal chemistry. 58(5)
- Publication Year :
- 2015
-
Abstract
- c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo[4,3-b]pyridine 9 with improved DMPK properties was discovered. Further elaboration of π–π stacking interactions and solvent accessible polar moieties led to a series of highly potent and selective type I c-Met inhibitors. On the basis of in vitro and in vivo pharmacological and pharmacokinetics studies, compound 46 was selected as a preclinical candidate for further anticancer drug development.
- Subjects :
- Models, Molecular
C-Met
Pyridines
Blotting, Western
Mice, Nude
Pharmacology
chemistry.chemical_compound
Mice
Pharmacokinetics
Cytochrome P-450 Enzyme System
In vivo
Cell Movement
Neoplasms
Drug Discovery
Potency
Animals
Humans
Tissue Distribution
Phosphorylation
Protein Kinase Inhibitors
Cell Proliferation
Molecular Structure
Hepatocyte Growth Factor
Cell Cycle
Rational design
Metabolic stability
Proto-Oncogene Proteins c-met
Combinatorial chemistry
Xenograft Model Antitumor Assays
In vitro
chemistry
Drug Design
Cancer cell
Microsomes, Liver
Molecular Medicine
Female
Signal Transduction
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 58
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....e768399830449048462d0fda783fdf77