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

Cho, Young and Whitehead, Lewis and Li, Jianke and Chen, Christine and Shultz, Michael and Jiang, Lei and Voegtle, Markus and Francotte, Eric and Richert, Paul and Wagner, Beatrix and Traebert, Martin and lu, qiang and Cao, Xueying and Dumotier, Berengere and Fejzo, Jasna and Rajan, Srinivasan and Wang, Ping and Yan-Neale, Yan and Shao, Wenlin and Atadja, Peter (2010) Conformational Refinement of Hydroxamate-Based Histone Deacetylase Inhibitors and Exploration of 3-Piperidin-3-yl-indole Analogues of Dacinostat (LAQ824). Journal of Medicinal Chemistry, 53 (7). pp. 2952-2963. ISSN 0022-2623

Abstract

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.

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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2199

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