Design, synthesis, and structure-activity relationships of spirolactones bearing 2-ureidobenzothiophene as acetyl-CoA carboxylases inhibitors

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6314-8. doi: 10.1016/j.bmcl.2011.08.117. Epub 2011 Sep 6.

Abstract

The co-crystal structure of the human acetyl-coenzyme A 2 (ACC2) carboxyl transferase domain and the reported compound CP-640186 (1b) suggested that two carbonyl groups are essential for potent ACC2 inhibition. By focusing on enhancing the interactions between the two carbonyl groups and the amino acid residues Gly(2162) and Glu(2230), we used ligand- and structure-based drug design to discover spirolactones bearing a 2-ureidobenzothiophene moiety.

MeSH terms

  • Acetyl-CoA Carboxylase / antagonists & inhibitors*
  • Crystallization
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Spironolactone / chemical synthesis*
  • Spironolactone / chemistry
  • Spironolactone / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Spironolactone
  • Acetyl-CoA Carboxylase