Abstract
A series of benzoxazinones was synthesized and evaluated as novel long chain fatty acid elongase 6 (ELOVL6) inhibitors. Exploration of the SAR of the UHTS lead 1a led to the identification of (S)-1y that possesses a unique chiral quarternary center and a pyrazole ring as critical pharmacophore elements. Compound (S)-1y showed potent and selective inhibitory activity toward human ELOVL6 while displaying potent inhibitory activity toward both mouse ELOVL3 and 6 enzymes. Compound (S)-1y showed acceptable pharmacokinetic profiles after oral dosing in mice. Furthermore, (S)-1y significantly suppressed the elongation of target fatty acids in mouse liver at 30 mg/kg oral dosing.
MeSH terms
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Acetyltransferases / antagonists & inhibitors*
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Acetyltransferases / metabolism
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Administration, Oral
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Animals
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Benzoxazines / administration & dosage*
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Benzoxazines / chemical synthesis
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Benzoxazines / chemistry
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Benzoxazines / pharmacology*
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Cell Line, Tumor
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Drug Discovery*
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Enzyme Inhibitors / administration & dosage*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Fatty Acid Elongases
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Fatty Acids / blood
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Fatty Acids / metabolism
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Humans
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Liver / drug effects
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Liver / metabolism
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Male
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Mice
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Structure-Activity Relationship
Substances
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Benzoxazines
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ELOVL3 protein, human
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ELOVL6 protein, human
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Elovl3 protein, mouse
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Elovl6 protein, mouse
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Enzyme Inhibitors
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Fatty Acids
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Acetyltransferases
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Fatty Acid Elongases