Discovery of potent and liver-selective stearoyl-CoA desaturase (SCD) inhibitors in an acyclic linker series

Bioorg Med Chem Lett. 2012 Jan 1;22(1):623-7. doi: 10.1016/j.bmcl.2011.10.070. Epub 2011 Oct 28.

Abstract

Elevated levels of stearoyl-CoA desaturase (SCD) activity have been implicated in metabolic disorders such as obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed inhibitors, our research efforts have been focused on the search for new liver-targeting compounds. This work has led to the discovery of novel, potent and liver-selective acyclic linker SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.

MeSH terms

  • Acetates / pharmacology
  • Animals
  • Chemistry, Pharmaceutical / methods*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Hydrolysis
  • Inhibitory Concentration 50
  • Liver / enzymology*
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Models, Chemical
  • Obesity / drug therapy
  • Stearoyl-CoA Desaturase / antagonists & inhibitors*
  • Stearoyl-CoA Desaturase / chemistry
  • Structure-Activity Relationship
  • Tetrazoles / pharmacology

Substances

  • (5-(3-(4-(2-bromo-5-fluorophenoxy)piperidin-1-yl)isoxazol-5-yl)-2H-tetrazol-2-yl)acetic acid
  • Acetates
  • Enzyme Inhibitors
  • Tetrazoles
  • Stearoyl-CoA Desaturase