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

Hiroki Nishii; Takashi Chiba; Kenji Morikami; Takaaki A Fukami; Hiroshi Sakamoto; Kwangseok Ko; Hiroshi Koyano

doi:10.1016/j.bmcl.2009.12.109

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

Bioorg Med Chem Lett. 2010 Feb 15;20(4):1405-9. doi: 10.1016/j.bmcl.2009.12.109. Epub 2010 Jan 4.

Authors

Hiroki Nishii¹, Takashi Chiba, Kenji Morikami, Takaaki A Fukami, Hiroshi Sakamoto, Kwangseok Ko, Hiroshi Koyano

Affiliation

¹ Department of Chemistry Research 2, Chugai Pharmaceutical Co, Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.

PMID: 20093027
DOI: 10.1016/j.bmcl.2009.12.109

Abstract

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Crizotinib
Crystallography, X-Ray
Humans
Inhibitory Concentration 50
Models, Molecular
Oxyquinoline / chemical synthesis*
Oxyquinoline / chemistry
Oxyquinoline / pharmacology
Piperidines / chemistry*
Piperidines / pharmacology
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Pyrazoles
Pyridines / chemistry*
Pyridines / pharmacology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Piperidines
Protein Kinase Inhibitors
Pyrazoles
Pyridines
Crizotinib
Oxyquinoline
Proto-Oncogene Proteins c-met