1189153-01-2Relevant academic research and scientific papers
Conformational refinement of hydroxamate-based histone deacetylase inhibitors and exploration of 3-piperidin-3-ylindole analogues of dacinostat (LAQ824)
Cho, Young Shin,Whitehead, Lewis,Li, Jianke,Chen, Christine H.-T.,Jiang, Lei,V?gtle, Markus,Francotte, Eric,Richert, Paul,Wagner, Trixie,Traebert, Martin,Lu, Qiang,Cao, Xueying,Dumotier, Berengere,Fejzo, Jasna,Rajan, Srinivasan,Wang, Ping,Yan-Neale, Yan,Shao, Wenlin,Atadja, Peter,Shultz, Michael
experimental part, p. 2952 - 2963 (2010/08/06)
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.
HYDROXAMATE-BASED INHIBITORS OF DEACETYLASES B
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Page/Page column 42, (2009/10/06)
The present teachings relate to compounds of Formula I: and pharmaceutically acceptable salts, hydrates, esters, and prodrugs thereof, wherein R1, R2, R3, Y, Z, and are as defined herein. The present teachings also provide methods of preparing compounds of Formula I and methods of using compounds of Formula I in treating, inhibiting, or preventing pathologic conditions or disorders mediated wholly or in part by deacetylases.
