Phenoxy thiazole derivatives as potent and selective acetyl-CoA carboxylase 2 inhibitors: Modulation of isozyme selectivity by incorporation of phenyl ring substituents

Bioorg Med Chem Lett. 2007 Apr 1;17(7):1961-5. doi: 10.1016/j.bmcl.2007.01.022. Epub 2007 Jan 19.

Abstract

A phenyl ring substitution strategy was employed to optimize the ACC2 potency and selectivity profiles of a recently discovered phenoxy thiazolyl series of acetyl-CoA carboxylase inhibitors. Ring substituents were shown to dramatically affect isozyme selectivity. Modifications that generally impart high levels of ACC2 selectivity (>3000-fold) while maintaining excellent ACC2 potency (IC50s approximately 9-20 nM) were identified.

MeSH terms

  • Acetyl-CoA Carboxylase / antagonists & inhibitors*
  • Acetyl-CoA Carboxylase / chemistry
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hypoglycemic Agents / chemistry
  • Inhibitory Concentration 50
  • Isoenzymes / chemistry
  • Models, Chemical
  • Molecular Conformation
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Isoenzymes
  • ACACB protein, human
  • Acetyl-CoA Carboxylase