Abstract
Novel indoledione derivatives were synthesized and evaluated as long chain fatty acid elongase 6 (ELOVL6) inhibitors. Systematic optimization of an indole class of lead 1 led to the identification of potent ELOVL6 selective inhibitors. Representative inhibitor 37 showed sustained plasma exposure and good liver penetrability in mice. After oral administration, 37 potently inhibited ELOVL6 activity in the liver in mice.
MeSH terms
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Acetyltransferases / antagonists & inhibitors*
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Administration, Oral
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Animals
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Drug Stability
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Enzyme Inhibitors / blood
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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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Fatty Acid Elongases
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Indoles / chemical synthesis*
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Indoles / pharmacology
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Liver / metabolism
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Mice
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Structure-Activity Relationship
Substances
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Elovl6 protein, mouse
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Enzyme Inhibitors
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Indoles
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Acetyltransferases
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Fatty Acid Elongases