期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 23, 期 23, 页码 6363-6369出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.09.061
关键词
Colony-stimulating factor-1 receptor; FMS; Macrophage colony-stimulating factor; KIT; Hypocellularity; Anti-inflammatory; Rheumatoid arthritis
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. (C) 2013 Elsevier Ltd. All rights reserved.
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