Discovery of novel FMS kinase inhibitors as anti-inflammatory agents

Discovery of a series of novel 2,4-disubstituted arylamides as potential anti-inflammatory agents is described. Compound 8 was utilized in an in vivo CIA model to evaluate the therapeutic potential of FMS inhibition. The optimization of the arylamide lead 2 resulted in identification of a highly pot...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2008-03, Vol.18 (5), p.1642-1648
Hauptverfasser:	Illig, Carl R., Chen, Jinsheng, Wall, Mark J., Wilson, Kenneth J., Ballentine, Shelley K., Rudolph, M. Jonathan, DesJarlais, Renee L., Chen, Yanmin, Schubert, Carsten, Petrounia, Ioanna, Crysler, Carl S., Molloy, Christopher J., Chaikin, Margery A., Manthey, Carl L., Player, Mark R., Tomczuk, Bruce E., Meegalla, Sanath K.
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Anti-inflammatory activity Anti-Inflammatory Agents - chemistry Anti-Inflammatory Agents - pharmacology Arthritis - chemically induced Arthritis - drug therapy Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Collagen Colony stimulating factor-1 CSF-1R Dose-Response Relationship, Drug FMS M-CSF Macrophages Medical sciences Mice Models, Molecular Molecular Structure Pharmacology. Drug treatments Receptor, Macrophage Colony-Stimulating Factor - antagonists & inhibitors Structure-Activity Relationship Time Factors
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Zusammenfassung:	Discovery of a series of novel 2,4-disubstituted arylamides as potential anti-inflammatory agents is described. Compound 8 was utilized in an in vivo CIA model to evaluate the therapeutic potential of FMS inhibition. The optimization of the arylamide lead 2 resulted in identification of a highly potent series of 2,4-disubstituted arylamides. Compound 8 (FMS kinase IC 50 = 0.0008 μM) served as a proof-of-concept candidate in a collagen-induced model of arthritis in mice.
ISSN:	0960-894X 0968-0896 1464-3405 1464-3391
DOI:	10.1016/j.bmcl.2008.01.059