4-Bicyclic heteroaryl-piperidine derivatives as potent, orally bioavailable stearoyl-CoA desaturase-1 (SCD1) inhibitors: part 2. Pyridazine-based analogs

Bioorg Med Chem Lett. 2014 Mar 1;24(5):1437-41. doi: 10.1016/j.bmcl.2013.12.075. Epub 2013 Dec 27.

Abstract

Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition.

Keywords: Desaturation index; SCD1 inhibitors; Stearoyl-CoA desaturase; obesity.

MeSH terms

  • Administration, Oral
  • Animals
  • Body Weight / drug effects
  • Bridged Bicyclo Compounds / chemistry*
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Half-Life
  • Humans
  • Mice
  • Microsomes, Liver / metabolism
  • Obesity / drug therapy
  • Pyridazines / chemistry*
  • Pyridazines / pharmacokinetics
  • Pyridazines / pharmacology
  • Pyridazines / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Zucker
  • Stearoyl-CoA Desaturase / antagonists & inhibitors*
  • Stearoyl-CoA Desaturase / metabolism
  • Structure-Activity Relationship

Substances

  • Bridged Bicyclo Compounds
  • Enzyme Inhibitors
  • Pyridazines
  • pyridazine
  • Stearoyl-CoA Desaturase