Abstract
We have recently reported on a novel class of histone deacetylase (HDAC) inhibitors bearing a sulfamide group as the zinc-binding unit. Herein, we report on the synthesis of sulfamide based inhibitors designed around a lysine scaffold and their structure-activity relationships against HDAC1 and HDAC6 isotypes as well as 293T cells. Our efforts led us to an improvement of the originally disclosed lysine-based sulfamide, 2a to compound 12h which has equal potency in enzyme and cell-based assays as well as enhanced metabolic stability and PK profile.
MeSH terms
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Animals
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology*
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Carrier Proteins / chemistry
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Cell Line
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Histone Deacetylase Inhibitors*
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Histone Deacetylases / metabolism
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Humans
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Lysine / chemistry
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Rats
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology*
Substances
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Benzimidazoles
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Carrier Proteins
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Enzyme Inhibitors
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Histone Deacetylase Inhibitors
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Protein Isoforms
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Sulfonamides
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zinc-binding protein
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Histone Deacetylases
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Lysine