Discovery and Optimization of Triazolopyridazines as Potent and Selective Inhibitors of the c-Met Kinase

Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway has been observed in multiple tumor types. Here...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-05, Vol.51 (10), p.2879-2882
Main Authors: Albrecht, Brian K, Harmange, Jean-Christophe, Bauer, David, Berry, Loren, Bode, Christiane, Boezio, Alessandro A, Chen, April, Choquette, Deborah, Dussault, Isabelle, Fridrich, Cary, Hirai, Satoko, Hoffman, Doug, Larrow, Jay F, Kaplan-Lefko, Paula, Lin, Jasmine, Lohman, Julia, Long, Alexander M, Moriguchi, Jodi, O’Connor, Anne, Potashman, Michele H, Reese, Monica, Rex, Karen, Siegmund, Aaron, Shah, Kavita, Shimanovich, Roman, Springer, Stephanie K, Teffera, Yohannes, Yang, Yajing, Zhang, Yihong, Bellon, Steven F
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
Crystallography, X-Ray
General aspects
Hepatocyte Growth Factor - physiology
In Vitro Techniques
Medical sciences
Mice
Microsomes, Liver - metabolism
Models, Molecular
Molecular Structure
Pharmacology. Drug treatments
Phosphorylation
Proto-Oncogene Proteins c-met - antagonists & inhibitors
Proto-Oncogene Proteins c-met - chemistry
Proto-Oncogene Proteins c-met - metabolism
Pyridazines - chemical synthesis
Pyridazines - chemistry
Pyridazines - pharmacokinetics
Pyridazines - pharmacology
Rats
Structure-Activity Relationship
Triazoles - chemical synthesis
Triazoles - chemistry
Triazoles - pharmacokinetics
Triazoles - pharmacology
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Summary:Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway has been observed in multiple tumor types. Herein we report the discovery of potent and selective triazolopyridazine small molecules that inhibit c-Met activity.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm800043g