SAR and optimization of thiazole analogs as potent stearoyl-CoA desaturase inhibitors

Bioorg Med Chem Lett. 2010 Mar 1;20(5):1593-7. doi: 10.1016/j.bmcl.2010.01.083. Epub 2010 Jan 21.

Abstract

Elevated stearoyl-CoA desaturase (SCD) activity has been linked to a number of metabolic disorders including obesity and type II diabetes. Compound 3j, a potent SCD inhibitor (human HepG2 IC(50)=1nM) was identified from the optimization of a lead thiazole compound MF-152 with over 100-fold improvement in potency. In a 4-week chronic oral dosing at 0.2mg/kg, 3j gave a robust 24% prevention of body weight gain in mice fed on a high fat diet accompanied with an improved metabolic profile on insulin and glucose levels.

MeSH terms

  • Administration, Oral
  • Animals
  • Dietary Fats
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / toxicity
  • Hep G2 Cells
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / toxicity
  • Mice
  • Mice, Inbred C57BL
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / chemistry*
  • Oxadiazoles / toxicity
  • Stearoyl-CoA Desaturase / antagonists & inhibitors*
  • Stearoyl-CoA Desaturase / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry*
  • Thiazoles / toxicity
  • Weight Gain

Substances

  • Dietary Fats
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Oxadiazoles
  • Thiazoles
  • Stearoyl-CoA Desaturase