Discovery of atrop fixed alkoxy-aminobenzhydrol derivatives: novel, highly potent and orally efficacious squalene synthase inhibitors

Bioorg Med Chem. 2011 Sep 1;19(17):5207-24. doi: 10.1016/j.bmc.2011.07.007. Epub 2011 Jul 13.

Abstract

We have recently reported the discovery of the new benzhydrol template, which has a highly potent inhibitory activity for squalene synthase, as typified by compound 1 (SSI IC(50)=0.85 nM). However, it was composed of a pair of easy rotatable atropisomers. In the effort to fix the isomerization, a highly potent alkoxy-aminobenzhydrol scaffold was developed. Some of these acquired compounds demonstrating strong cholesterol synthesis inhibitory activities in a rat hepatic cell. Moreover, two of the series compounds exhibited specific plasma lipid-lowering effects in in vivo animal models.

MeSH terms

  • Administration, Oral
  • Animals
  • Anticholesteremic Agents / chemical synthesis
  • Anticholesteremic Agents / chemistry*
  • Anticholesteremic Agents / pharmacokinetics
  • Benzhydryl Compounds / chemical synthesis
  • Benzhydryl Compounds / chemistry*
  • Benzhydryl Compounds / pharmacokinetics
  • Binding Sites
  • Callithrix
  • Computer Simulation
  • Cricetinae
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Farnesyl-Diphosphate Farnesyltransferase / antagonists & inhibitors*
  • Farnesyl-Diphosphate Farnesyltransferase / metabolism
  • Female
  • Hepatocytes / drug effects
  • Isomerism
  • Male
  • Models, Animal
  • Rats
  • Structure-Activity Relationship

Substances

  • Anticholesteremic Agents
  • Benzhydryl Compounds
  • Enzyme Inhibitors
  • Farnesyl-Diphosphate Farnesyltransferase
  • benzohydrol