Design of small molecule inhibitors of acetyl-CoA carboxylase 1 and 2 showing reduction of hepatic malonyl-CoA levels in vivo in obese Zucker rats

Bioorg Med Chem. 2011 May 15;19(10):3039-53. doi: 10.1016/j.bmc.2011.04.014. Epub 2011 Apr 13.

Abstract

Inhibition of acetyl-CoA carboxylases has the potential for modulating long chain fatty acid biosynthesis and mitochondrial fatty acid oxidation. Hybridization of weak inhibitors of ACC2 provided a novel, moderately potent but lipophilic series. Optimization led to compounds 33 and 37, which exhibit potent inhibition of human ACC2, 10-fold selectivity over inhibition of human ACC1, good physical and in vitro ADME properties and good bioavailability. X-ray crystallography has shown this series binding in the CT-domain of ACC2 and revealed two key hydrogen bonding interactions. Both 33 and 37 lower levels of hepatic malonyl-CoA in vivo in obese Zucker rats.

MeSH terms

  • Acetyl-CoA Carboxylase / antagonists & inhibitors*
  • Acetyl-CoA Carboxylase / metabolism
  • Animals
  • Crystallography, X-Ray
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / enzymology
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Fatty Acids / metabolism
  • Humans
  • Liver / drug effects
  • Liver / enzymology
  • Male
  • Malonyl Coenzyme A / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Obesity / drug therapy*
  • Obesity / enzymology
  • Rats
  • Rats, Zucker
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacokinetics
  • Small Molecule Libraries / pharmacology*
  • Small Molecule Libraries / therapeutic use
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Fatty Acids
  • Small Molecule Libraries
  • Malonyl Coenzyme A
  • Acetyl-CoA Carboxylase