Abstract
Long chain fatty acid elongase 6 (ELOVL6) catalyzes the elongation of long chain fatty acyl-CoAs and is a potential target for the treatment of metabolic disorders. The ultrahigh throughput screen of our corporate chemical collections resulted in the identification of a novel 3-sulfonyl-8-azabicyclo[3.2.1]octane class of ELOVL6 inhibitor 1a. Optimization of lead 1a led to the identification of the potent, selective, and orally available ELOVL6 inhibitor 1w.
MeSH terms
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Acetyltransferases / antagonists & inhibitors*
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Animals
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Cell Line
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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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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Hepatocytes / drug effects
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Hepatocytes / enzymology
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Humans
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Inhibitory Concentration 50
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Liver / drug effects
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Liver / enzymology
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Male
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Mice
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Octanes / chemical synthesis*
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Octanes / chemistry
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Octanes / pharmacokinetics
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Octanes / pharmacology*
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Rats
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Structure-Activity Relationship
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Sulfones / chemical synthesis*
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Sulfones / chemistry*
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Sulfones / pharmacokinetics
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Sulfones / pharmacology*
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Tropanes / chemical synthesis*
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Tropanes / chemistry*
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Tropanes / pharmacokinetics
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Tropanes / pharmacology*
Substances
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ELOVL6 protein, human
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Elovl6 protein, mouse
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Enzyme Inhibitors
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Octanes
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Sulfones
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Tropanes
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Acetyltransferases
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Fatty Acid Elongases