Abstract
A structurally novel acetyl-CoA carboxylase (ACC) inhibitor is identified from high-throughput screening. A preliminary structure-activity relationship study led to the discovery of potent dual ACC1/ACC2 and ACC2 selective inhibitors against human recombinant ACC1 and ACC2. Selective ACC2 inhibitors exhibited IC50<20 nM and >1000-fold selectivity against ACC1. (S)-Enantiomer 9p exhibited high ACC2 activity and lowered muscle malonyl-CoA dose-dependently in acute rodent studies, whereas (R)-enantiomer 9o was weak and had no effect on the malonyl-CoA level.
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 / pharmacokinetics
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Alkynes / pharmacology
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Animals
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Cell Line
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Humans
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / pharmacology
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In Vitro Techniques
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / genetics
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Malonyl Coenzyme A / metabolism
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism
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Rats
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Rats, Sprague-Dawley
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / genetics
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Stereoisomerism
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Structure-Activity Relationship
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Thiazoles / chemical synthesis*
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology
Substances
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Alkynes
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Hypoglycemic Agents
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Isoenzymes
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Recombinant Proteins
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Thiazoles
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Malonyl Coenzyme A
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Acetyl-CoA Carboxylase