Abstract
The structure-activity relationship study focused on the polar region of the HTS hit A-80040 (1) producing several series of potent and selective ACC2 inhibitors. The SAR suggests a compact lipophilic pocket that does not tolerate polar and ionic groups. Replacement of the hydroxyurea group with isoxazoles improves ACC2 selectivity while maintaining potency. Variations at the propargylic site of 11a reduce ACC2 potency.
MeSH terms
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Acetyl-CoA Carboxylase / antagonists & inhibitors*
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Acetyl-CoA Carboxylase / genetics
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Alkynes / chemical synthesis*
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Alkynes / pharmacology*
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Chemical Phenomena
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Chemistry, Physical
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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Humans
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Hydroxyurea / chemistry
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Isoxazoles / chemical synthesis
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Isoxazoles / pharmacology
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Molecular Conformation
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Recombinant Proteins / metabolism
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Structure-Activity Relationship
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Thiazoles / chemical synthesis*
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Thiazoles / pharmacology*
Substances
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Alkynes
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Enzyme Inhibitors
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Isoxazoles
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Recombinant Proteins
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Thiazoles
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Acetyl-CoA Carboxylase
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Hydroxyurea