| Literature DB >> 24900421 |
Gang Liu1, Brian T Campbell1, Mark W Holladay1, Julia M Ford Pulido1, Helen Hua1, Dana Gitnick1, Michael F Gardner1, Joyce James1, Mike A Breider1, Daniel Brigham1, Barbara Belli1, Robert C Armstrong1, Daniel K Treiber1.
Abstract
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 pharmacokinetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the α-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.Entities:
Keywords: AC710; acute myeloid leukemia (AML); cancer bone metastasis; colony-stimulating factor-1 receptor (CSF1R) inhibitor; feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3); inflammatory arthritis; platelet-derived growth factor receptor (PDGFR)-family kinases
Year: 2012 PMID： 24900421 PMCID： PMC4025831 DOI： 10.1021/ml300214g
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345