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

• DOI: 10.1021/jm100007m
• Publication Date: 2010-03-05T14:44:19Z
• Authors: Young Shin Cho; Lewis Whitehead; Jianke Li; Christine H.-T. Chen; Lei Jiang; Markus Vögtle; Eric Francotte; Paul Richert; Trixie Wagner; Martin Traebert; Qiang Lu; Xueying Cao; Berengere Dumotier; Jasna Fejzo; Srinivasan Rajan; Ping Wang; Yan Yan-Neale; Wenlin Shao; Peter Atadja; Michael Shultz
• Keywords: Models, Molecular; 0303 health sciences; Indoles; Molecular Conformation; Stereoisomerism; Hydroxamic Acids; Histone Deacetylases; 3. Good health; Histone Deacetylase Inhibitors; Inhibitory Concentration 50; 03 medical and health sciences; Cell Line, Tumor; Humans; Cell Proliferation

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.