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Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases.

Autor(es): Liu, Gang; Campbell, Brian T; Holladay, Mark W; Ford Pulido, Julia M; Hua, Helen; Gitnick, Dana; Gardner, Michael F; James, Joyce; Breider, Mike A; Brigham, Daniel; Belli, Barbara; Armstrong, Robert C; Treiber, Daniel K
Fonte: ACS Med Chem Lett;3(12): 997-1002, 2012 Dec 13.
Artigo [ PMID: 24900421 ] Idioma(s): Inglês
Publicação: Artigo de Revista
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.