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

被引：35

作者：

Cho, Young Shin ^{[1
]}

Whitehead, Lewis ^{[1
]}

Li, Jianke ^{[1
]}

Chen, Christine H-T. ^{[1
]}

Jiang, Lei ^{[1
]}

Voegtle, Markus ^{[2
]}

Francotte, Eric ^{[2
]}

Richert, Paul ^{[2
]}

Wagner, Trixie ^{[2
]}

Traebert, Martin ^{[2
]}

Lu, Qiang ^{[1
]}

Cao, Xueying ^{[1
]}

Dumotier, Berengere ^{[2
]}

Fejzo, Jasna ^{[1
]}

Rajan, Srinivasan ^{[1
]}

Wang, Ping ^{[1
]}

Yan-Neale, Yan ^{[1
]}

Shao, Wenlin ^{[1
]}

Atadja, Peter ^{[1
]}

Shultz, Michael ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[2] Werk Klybeck, CH-4002 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 07期

关键词：

IN-VIVO; POTASSIUM CHANNELS; ANTITUMOR-ACTIVITY; SPIRUCHOSTATIN-A; HERG; POTENT; DRUG; DEPSIPEPTIDE; PROLONGATION; ENANTIOMERS;

D O I：

10.1021/jm100007m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 h ERG binding. Separation of racemate 30 afforded 32, the R enantiomer, which demonstrated improved potency in both enzyme and cellular assays compared to dacinostat.

引用

页码：2952 / 2963

页数：12

共 37 条

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