Abstract
We describe the discovery of histone deacetylase (HDACs) 1, 2, and 3 inhibitors with ethyl ketone as the zinc-binding group. These HDACs 1, 2, and 3 inhibitors have good enzymatic and cellular activity. Their serum shift in cellular potency has been minimized, and selectivity against hERG has been improved. They are also highly selective over HDACs 6 and 8. These inhibitors contain a variety of substituted heterocycles on the imidazole or oxazole scaffold. Compounds 31 and 48 stand out due to their good potency, high selectivity over HDACs 6 and 8, reduced hERG activity, optimized serum shift in cellular potency, and good rat and dog PK profiles.
MeSH terms
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Animals
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Dogs
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Drug Evaluation, Preclinical
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ERG1 Potassium Channel / metabolism*
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HIV-1 / physiology*
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Half-Life
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Histone Deacetylase 1 / antagonists & inhibitors
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Histone Deacetylase 1 / metabolism
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Histone Deacetylase 2 / antagonists & inhibitors
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Histone Deacetylase 2 / metabolism
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Histone Deacetylase Inhibitors / chemistry*
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Histone Deacetylase Inhibitors / metabolism
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Histone Deacetylase Inhibitors / pharmacology
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Histone Deacetylases / chemistry
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Histone Deacetylases / metabolism*
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Humans
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Imidazoles / chemistry
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Ketones / chemistry*
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Oxazoles / 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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Virus Activation / drug effects
Substances
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ERG1 Potassium Channel
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Histone Deacetylase Inhibitors
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Imidazoles
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Ketones
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Oxazoles
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Protein Isoforms
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imidazole
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Histone Deacetylase 1
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Histone Deacetylase 2
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Histone Deacetylases
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histone deacetylase 3