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

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• 作者：Gang Liu ; Brian T. Campbell ; Mark W. Holladay ; Julia M. Ford Pulido ; Helen Hua ; Dana Gitnick ; Michael F. Gardner ; Joyce James ; Mike A. Breider ; Daniel Brigham ; Barbara Belli ; Robert C. Armstrong ; Daniel K. Treiber
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：3
• 期：12
• 页码：997-1002
• 全文大小：322K
• 年卷期：v.3,no.12(December 13, 2012)
• ISSN：1948-5875

文摘

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 伪-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.

Keywords:

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