title: Conformational refinement of hydroxamate-based histone deacetylase inhibitors and exploration of 3-piperidin-3-ylindole analogues of dacinostat (LAQ824).
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.
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Young Shin
authors.initials: YS
authors.lastname: Cho
authors.forename: Lewis
authors.initials: L
authors.lastname: Whitehead
authors.forename: Jianke
authors.initials: J
authors.lastname: Li
authors.forename: Christine H-T
authors.initials: CH
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.forename: Markus
authors.initials: M
authors.lastname: Vögtle
authors.forename: Eric
authors.initials: E
authors.lastname: Francotte
authors.forename: Paul
authors.initials: P
authors.lastname: Richert
authors.forename: Trixie
authors.initials: T
authors.lastname: Wagner
authors.forename: Martin
authors.initials: M
authors.lastname: Traebert
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lu
authors.forename: Xueying
authors.initials: X
authors.lastname: Cao
authors.forename: Berengere
authors.initials: B
authors.lastname: Dumotier
authors.forename: Jasna
authors.initials: J
authors.lastname: Fejzo
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Rajan
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan-Neale
authors.forename: Wenlin
authors.initials: W
authors.lastname: Shao
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Michael
authors.initials: M
authors.lastname: Shultz
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; C477361:LAQ824; D006655:Histone Deacetylases