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: hERG; Hydroxamic acid; Lipophilicity; Moiety; Natural product

Inspired by natural product HDAC inhibitors, we prepared a series of conformationally restrained inhibitors based on the hydroxamic acid dacinostat (LAQ824, 7). Several scaffolds with improved biochemical and cellular potency, as well attenuated hERG inhibition, were identified, suggesting that introduction molecular rigidity is viable strategy to enhance binding mitigate liability. Further SAR studies around 3-piperidin-3-ylindole moiety resulted in discovery compound 30, for which unique conformation was speculated contribute overcoming increased lipophilicity attenuating binding. Separation racemate 30 afforded 32, R enantiomer, demonstrated potency both enzyme assays compared dacinostat.