Discovery of potent, selective, orally bioavailable stearoyl-CoA desaturase 1 inhibitors

J Med Chem. 2007 Jun 28;50(13):3086-100. doi: 10.1021/jm070219p. Epub 2007 May 27.


Stearoyl-CoA desaturase 1 (SCD1) catalyzes the committed step in the biosynthesis of monounsaturated fatty acids from saturated, long-chain fatty acids. Studies with SCD1 knockout mice have established that these animals are lean and protected from leptin deficiency-induced and diet-induced obesity, with greater whole body insulin sensitivity than wild-type animals. In this work, we have discovered a series of potent, selective, orally bioavailable SCD1 inhibitors based on a known pyridazine carboxamide template. The representative lead inhibitor 28c also demonstrates excellent cellular activity in blocking the conversion of saturated long-chain fatty acid-CoAs (LCFA-CoAs) to monounsaturated LCFA-CoAs in HepG2 cells.

MeSH terms

  • Acyl Coenzyme A / metabolism
  • Animals
  • Biological Availability
  • Cell Line, Tumor
  • Humans
  • In Vitro Techniques
  • Mice
  • Microsomes, Liver / metabolism
  • Oxadiazoles / chemical synthesis*
  • Oxadiazoles / pharmacokinetics
  • Oxadiazoles / pharmacology
  • Pyridazines / chemical synthesis*
  • Pyridazines / pharmacokinetics
  • Pyridazines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Stearoyl-CoA Desaturase / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Acyl Coenzyme A
  • CAY10566
  • Oxadiazoles
  • Pyridazines
  • SCD1 protein, human
  • Scd1 protein, mouse
  • Stearoyl-CoA Desaturase