Synthesis and evaluation of novel 3,4,6-substituted 2-quinolones as FMS kinase inhibitors

A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as FMS inhibitors. A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2008-03, Vol.18 (6), p.2097-2102
Hauptverfasser:	Wall, Mark J., Chen, Jinsheng, Meegalla, Sanath, Ballentine, Shelley K., Wilson, Kenneth J., DesJarlais, Renee L., Schubert, Carsten, Chaikin, Margery A., Crysler, Carl, Petrounia, Ioanna P., Donatelli, Robert R., Yurkow, Edward J., Boczon, Lisa, Mazzulla, Marie, Player, Mark R., Patch, Raymond J., Manthey, Carl L., Molloy, Christopher, Tomczuk, Bruce, Illig, Carl R.
Format:	Artikel
Sprache:	eng
Schlagworte:	2-Quinolones Administration, Oral Animals Antineoplastic agents Biological and medical sciences Biological Availability Bones, joints and connective tissue. Antiinflammatory agents Cell Proliferation - drug effects cFMS Colony-stimulating factor-1 receptor CSF-1 Fluorescence Polarization FMS General aspects Genes, fos - genetics M-CSF Macrophage Colony-Stimulating Factor - metabolism Macrophages - drug effects Medical sciences Mice Mice, Inbred C57BL Molecular Structure Pharmacology. Drug treatments Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacology Quinolones - chemical synthesis Quinolones - pharmacokinetics Quinolones - pharmacology Rats Receptor, Macrophage Colony-Stimulating Factor - antagonists & inhibitors Receptor, Macrophage Colony-Stimulating Factor - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics RNA, Messenger - metabolism Spleen - metabolism Structure-Activity Relationship
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Zusammenfassung:	A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as FMS inhibitors. A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3 H-imidazol-4-yl)-2-quinolone-6-carbonitrile 21b, has an IC 50 of 2.5 nM in an in vitro assay and 5.0 nM in a bone marrow-derived macrophage cellular assay. Inhibition of FMS signaling in vivo was also demonstrated in a mouse pharmacodynamic model.
ISSN:	0960-894X 0968-0896 1464-3405 1464-3391
DOI:	10.1016/j.bmcl.2008.01.088