Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 3, Issue 12, Pages 997-1002Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml300214g
Keywords
platelet-derived growth factor receptor (PDGFR)-family kinases; feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3); colony-stimulating factor-1 receptor (CSFIR) inhibitor; acute myeloid leukemia (AML); cancer bone metastasis; inflammatory arthritis; AC710
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A series of potent, selective platelet-derived growth factor receptor-family kinase inhibitors was optimized starting from a globally selective lead molecule 4 through structural modifications aimed at improving the physiochemical and pharmacoldnetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the a-carbons of a solubilizing piperidine nitrogen resulted in advanced leads 22a and 22b. Results from a mouse tumor xenograft, a collagen-induced arthritis model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate.
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