Conformational Refinement of Hydroxamate-Based Histone Deacetylase Inhibitors and Exploration of 3-Piperidin-3-yl-indole Analogues of Dacinostat (LAQ824)
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Cho, Young, Whitehead, Lewis, Li, Jianke, Chen, Christine, Shultz, Michael, Jiang, Lei, Voegtle, Markus, Francotte, Eric, Richert, Paul, Wagner, Beatrix, Traebert, Martin, lu, qiang, Cao, Xueying, Dumotier, Berengere, Fejzo, Jasna, Rajan, Srinivasan, Wang, Ping, Yan-Neale, Yan, 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 |