- Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors
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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.
- Illig, Carl R.,Manthey, Carl L.,Meegalla, Sanath K.,Wall, Mark J.,Chen, Jinsheng,Wilson, Kenneth J.,Desjarlais, Renee L.,Ballentine, Shelley K.,Schubert, Carsten,Crysler, Carl S.,Chen, Yanmin,Molloy, Christopher J.,Chaikin, Margery A.,Donatelli, Robert R.,Yurkow, Edward,Zhou, Zhao,Player, Mark R.,Tomczuk, Bruce E.
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p. 6363 - 6369
(2013/11/19)
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- C-FMS KINASE INHIBITORS
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The invention is directed to compounds of Formula II: wherein A, R1, R2, R3, R4, X, Y and W are set forth in the specification, as well as solvates, hydrates, tautomers or pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase.
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