Bicyclic heteroaryl inhibitors of stearoyl-CoA desaturase: from systemic to liver-targeting inhibitors

Bioorg Med Chem Lett. 2011 Oct 1;21(19):5692-6. doi: 10.1016/j.bmcl.2011.08.037. Epub 2011 Aug 12.

Abstract

Optimization of a lead thiazole amide MF-152 led to the identification of potent bicyclic heteroaryl SCD1 inhibitors with good mouse pharmacokinetic profiles. In a view to target the liver for efficacy and to avoid SCD1 inhibition in the skin and eyes where adverse effects were previously observed in rodents, representative systemically-distributed SCD1 inhibitors were converted into liver-targeting SCD1 inhibitors.

MeSH terms

  • Amides
  • Animals
  • Drug Design*
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Drug Stability
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / toxicity
  • Liver / drug effects
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology*
  • Piperazines / toxicity
  • Rats
  • Stearoyl-CoA Desaturase / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology*
  • Thiazoles / toxicity

Substances

  • Amides
  • Enzyme Inhibitors
  • MF 152
  • Piperazines
  • Thiazoles
  • SCD1 protein, human
  • Stearoyl-CoA Desaturase