954424-85-2Relevant academic research and scientific papers
Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors
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.
, p. 6363 - 6369 (2013/11/19)
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.
INHIBITORS OF C-FMS KINASE
-
Page/Page column 72, (2008/06/13)
The invention is directed to compounds of Formula I: wherein Z, X, J, R2 and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including arthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.
