Conformational Refinement of Hydroxamate-Based Histone Deacetylase Inhibitors and Exploration of 3-Piperidin-3-ylindole Analogues of Dacinostat (LAQ824)

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• 作者：Young Shin Cho ; Lewis Whitehead ; Jianke Li ; Christine H.-T. Chen ; Lei Jiang ; Markus Vgtle ; Eric Francotte ; Paul Richert ; Trixie Wagner ; Martin Traebert ; Qiang Lu ; Xueying Cao ; Berengere Dumotier ; Jasn
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：April 8, 2010
• 年：2010
• 卷：53
• 期：7
• 页码：2952-2963
• 全文大小：1098K
• 年卷期：v.53,no.7(April 8, 2010)
• ISSN：1520-4804

文摘

Inspired by natural product HDAC inhibitors, we prepared a series of conformationally restrained HDAC inhibitors based on the hydroxamic acid dacinostat (LAQ824, 7). Several scaffolds with improved biochemical and cellular potency, as well as attenuated hERG inhibition, were identified, suggesting that the introduction of molecular rigidity is a viable strategy to enhance HDAC binding and mitigate hERG liability. Further SAR studies around a 3-piperidin-3-ylindole moiety resulted in the discovery of compound 30, for which a unique conformation was speculated to contribute to overcoming increased lipophilicity and attenuating hERG binding. Separation of racemate 30 afforded 32, the R enantiomer, which demonstrated improved potency in both enzyme and cellular assays compared to dacinostat.