Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2383-8. doi: 10.1016/j.bmcl.2009.04.091. Epub 2009 Apr 24.

Abstract

Screening Pfizer's compound library resulted in the identification of weak acetyl-CoA carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype.

MeSH terms

  • Acetyl-CoA Carboxylase / antagonists & inhibitors*
  • Acetyl-CoA Carboxylase / metabolism*
  • Animals
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Models, Molecular
  • Rats
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacokinetics
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Isoenzymes
  • Small Molecule Libraries
  • Acetyl-CoA Carboxylase