Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors

Carl R. Illig, Carl L. Manthey, Sanath K. Meegalla, Mark J. Wall, Jinsheng Chen, Kenneth J. Wilson, Renee L. Desjarlais, Shelley K. Ballentine, Carsten Schubert, Carl S. Crysler, Yanmin Chen, Christopher J. Molloy, Margery A. Chaikin, Robert R. Donatelli, Edward Yurkow, Zhao Zhou, Mark R. Player, Bruce E. Tomczuk

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats.

Original languageEnglish (US)
Pages (from-to)6363-6369
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number23
DOIs
StatePublished - Dec 1 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Keywords

  • Anti-inflammatory
  • Colony-stimulating factor-1 receptor
  • FMS
  • Hypocellularity
  • KIT
  • Macrophage colony-stimulating factor
  • Rheumatoid arthritis

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  • Cite this

    Illig, C. R., Manthey, C. L., Meegalla, S. K., Wall, M. J., Chen, J., Wilson, K. J., Desjarlais, R. L., Ballentine, S. K., Schubert, C., Crysler, C. S., Chen, Y., Molloy, C. J., Chaikin, M. A., Donatelli, R. R., Yurkow, E., Zhou, Z., Player, M. R., & Tomczuk, B. E. (2013). Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors. Bioorganic and Medicinal Chemistry Letters, 23(23), 6363-6369. https://doi.org/10.1016/j.bmcl.2013.09.061