Conformational refinement of hydroxamate-based histone deacetylase inhibitors and exploration of 3-piperidin-3-ylindole analogues of dacinostat (LAQ824).
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.
Cho
Young Shin
YS
Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Whitehead
Lewis
L
Li
Jianke
J
Chen
Christine H-T
CH
Jiang
Lei
L
Vögtle
Markus
M
Francotte
Eric
E
Richert
Paul
P
Wagner
Trixie
T
Traebert
Martin
M
Lu
Qiang
Q
Cao
Xueying
X
Dumotier
Berengere
B
Fejzo
Jasna
J
Rajan
Srinivasan
S
Wang
Ping
P
Yan-Neale
Yan
Y
Shao
Wenlin
W
Atadja
Peter
P
Shultz
Michael
M
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
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; C477361:LAQ824; D006655:Histone Deacetylases