Discovery of novel tricyclic compounds as squalene synthase inhibitors

Bioorg Med Chem. 2012 May 1;20(9):3072-93. doi: 10.1016/j.bmc.2012.02.054. Epub 2012 Mar 8.

Abstract

In the present article, we have reported the design, synthesis, and identification of highly potent benzhydrol derivatives as squalene synthase inhibitors (compound 1). Unfortunately, the in vivo efficacies of the compounds were not enough for acquiring the clinical candidate. We continued our investigation to obtain a more in vivo efficacious template than the benzhydrol template. In our effort, we focused on a benzoxazepine ring and designed a new tricyclic scaffold by the incorporation of heterocycle into it. Prepared pyrrolobenzoxazepine derivatives showed further efficient in vitro and in vivo activities.

MeSH terms

  • Administration, Oral
  • Animals
  • Anticholesteremic Agents / chemical synthesis
  • Anticholesteremic Agents / chemistry
  • Anticholesteremic Agents / pharmacology
  • Benzhydryl Compounds / chemical synthesis
  • Benzhydryl Compounds / chemistry
  • Benzhydryl Compounds / pharmacology
  • Binding Sites
  • Callithrix
  • Catalytic Domain
  • Cells, Cultured
  • Computer Simulation
  • Drug Design
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Farnesyl-Diphosphate Farnesyltransferase / antagonists & inhibitors*
  • Farnesyl-Diphosphate Farnesyltransferase / metabolism
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Rats
  • Structure-Activity Relationship

Substances

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