Discovery of 6-benzyloxyquinolines as c-Met selective kinase inhibitors

A novel quinoline derivative that selectively inhibits c-Met kinase was identified. The molecular design is based on a result of the analysis of a PF-2341066 ( 1)/c-Met cocrystal structure (PDB code: 2wgj). The kinase selectivity of the derivatives is discussed from the view point of the sequence ho...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-02, Vol.20 (4), p.1405-1409
Main Authors: Nishii, Hiroki, Chiba, Takashi, Morikami, Kenji, Fukami, Takaaki A., Sakamoto, Hiroshi, Ko, Kwangseok, Koyano, Hiroshi
Format: Article
Language:English
Subjects:
6-Benzyloxyquinolines
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
c-Met
Cell Line, Tumor
Cell Proliferation - drug effects
Crystallography, X-Ray
General aspects
Humans
Inhibitory Concentration 50
Kinase inhibitor
Medical sciences
Models, Molecular
Oxyquinoline - chemical synthesis
Oxyquinoline - chemistry
Oxyquinoline - pharmacology
Pharmacology. Drug treatments
Piperidines - chemistry
Piperidines - pharmacology
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-met - antagonists & inhibitors
Pyrazoles
Pyridines - chemistry
Pyridines - pharmacology
Structure-Activity Relationship
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Description
Summary:A novel quinoline derivative that selectively inhibits c-Met kinase was identified. The molecular design is based on a result of the analysis of a PF-2341066 ( 1)/c-Met cocrystal structure (PDB code: 2wgj). The kinase selectivity of the derivatives is discussed from the view point of the sequence homology of the kinases, the key interactions found in X-ray cocrystal structures, and the structure–activity relationship (SAR) obtained in this work.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.12.109